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Volume 18
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Pharmaceuticals, Volume 18, Issue 3 (March 2025) – 160 articles

Cover Story (view full-size image): Accurately predicting how strongly a drug binds to its target protein is essential in drug discovery. Current models rely on intensive protein–ligand interaction characterization but often lack reliability and generalizability. This challenge is exacerbated when structural data for these interactions are unavailable. To address this, we developed GNNSeq, a hybrid machine learning model that relies only on protein sequence data, removing the need for complex structural information. GNNSeq combines Graph Neural Networks (GNNs) with novel kernel-based switching algorithms to improve accuracy and efficiency. It processes large datasets quickly, making it ideal for scalable, cost-effective, virtual drug screening. Additional versions of GNNSeq hybridized with structure- and interaction-based models are freely available online. View this paper
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13 pages, 1718 KiB  
Article
Py-CoMSIA: An Open-Source Implementation of Comparative Molecular Similarity Indices Analysis in Python
by Christopher L. Haga, Crystal N. Le, Xue D. Yang and Donald G. Phinney
Pharmaceuticals 2025, 18(3), 440; https://doi.org/10.3390/ph18030440 - 20 Mar 2025
Viewed by 365
Abstract
Background/Objectives: The progression of three-dimensional (3D) quantitative structure–activity relationship (QSAR) methodologies has significantly contributed to the advancement of medicinal chemistry and pharmaceutical discovery. Comparative Molecular Similarity Indices Analysis (CoMSIA) is a widely used 3D-QSAR technique. However, its reliance on discontinued proprietary software creates [...] Read more.
Background/Objectives: The progression of three-dimensional (3D) quantitative structure–activity relationship (QSAR) methodologies has significantly contributed to the advancement of medicinal chemistry and pharmaceutical discovery. Comparative Molecular Similarity Indices Analysis (CoMSIA) is a widely used 3D-QSAR technique. However, its reliance on discontinued proprietary software creates accessibility challenges. This work aims to develop an open-source Python library to address these limitations and broaden access to grid-based 3D-QSAR methods. Methods: Py-CoMSIA was developed in Python using RDKit and NumPy for calculations and PyVista for visualizations. Results: Py-CoMSIA provides a functional open-source alternative to proprietary CoMSIA software. It successfully implements the core CoMSIA algorithm and generates comparable similarity indices, as demonstrated by testing several benchmarking datasets including the original CoMSIA steroid dataset. Conclusions: The Py-CoMSIA library addresses the accessibility issues associated with proprietary 3D-QSAR software by providing an open-source Python implementation of CoMSIA. This tool broadens access to complex grid-based 3D-QSAR methodologies and offers a flexible platform for integrating advanced statistical and machine learning techniques. Full article
(This article belongs to the Special Issue Application of 2D and 3D-QSAR Models in Drug Design)
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20 pages, 3618 KiB  
Article
Evaluation of the Anti-Aging Properties of Ethanolic Extracts from Selected Plant Species and Propolis by Enzyme Inhibition Assays and 2D/3D Cell Culture Methods
by F. Sezer Senol Deniz, Ilkay Erdogan Orhan, Przemyslaw Andrzej Filipek, Abdulselam Ertas, Ronald Gstir, Thomas Jakschitz and Günther Karl Bonn
Pharmaceuticals 2025, 18(3), 439; https://doi.org/10.3390/ph18030439 - 20 Mar 2025
Viewed by 308
Abstract
Background: Skin aging is a complex biological process affected by internal and external factors that disrupt the skin structure, especially in sun-exposed areas. Elastin and collagen in the dermis layer, responsible for the skin’s resistance and elasticity, have been the main subject [...] Read more.
Background: Skin aging is a complex biological process affected by internal and external factors that disrupt the skin structure, especially in sun-exposed areas. Elastin and collagen in the dermis layer, responsible for the skin’s resistance and elasticity, have been the main subject of research. Since tyrosinase (TYR) is an enzyme found in different organisms and plays an essential role in melanogenesis, inhibitors of this enzyme have been the target mechanism for skin-bleaching product research. Methods: We selected the plant species Cotinus coggygria Scop., Garcinia mangostana L., Pistacia vera L., Vitis vinifera L., and propolis, which exhibited activity against a minimum of three target enzymes—elastase, collagenase, and TYR—in our previous screening study to find the suitable raw material for a cosmetic product. In the current research, the extracts from these samples were tested through a cell-free enzyme assay using validated elastase, collagenase, and TYR inhibition kits. We also performed the safety and efficacy tests of the selected extracts with 2D/3D cell culture methods. Results: Our data revealed the propolis extract among the tested ones displayed remarkable anti-inflammatory activity in the 2D (NF-κB induction: 10.81%) and 3D assays. Cotinus coggygria leaf and Garcinia mangostana shell extracts exhibited anti-inflammatory activity in the 2D luciferase reporter assay via TNFα addition. C. coggygria leaf, V. vinifera (grape) seed, and propolis extracts were selected for testing in 3D cell culture methods based on the 2D cytotoxicity results with cell viability values of 54.75%, 93.19%, and 98.64% at 34.25 µg/mL, respectively. The general phytochemical profiles of these three extracts were examined in terms of 53 phenolic compounds with LC-MS/MS, revealing that quinic acid, epicatechin, and acacetin were the dominant phenolics among the tested ones. Conclusions: It is the first study conducted to evaluate the use of the extracts indicated above in cosmetics by employing procedures involving 3D cell culture. Full article
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11 pages, 2095 KiB  
Article
Short-Term Outcomes of Three Consecutive Monthly Loading Administrations of Aflibercept 8 Mg for Treatment-Naïve Exudative Age-Related Macular Degeneration
by Shuhei Hosoda, Yoichi Sakurada, Yoshiko Fukuda, Yumi Kotoda, Wataru Kikushima and Kenji Kashiwagi
Pharmaceuticals 2025, 18(3), 438; https://doi.org/10.3390/ph18030438 - 20 Mar 2025
Viewed by 494
Abstract
Background/Objectives: The aim was to investigate the short-term outcomes of three consecutive monthly aflibercept 8 mg administrations for treatment-naïve eyes with exudative age-related macular degeneration (AMD). Methods: Twenty-one eyes with exudative AMD were included (type 1 macular neovascularization: eleven eyes; type 2 macular [...] Read more.
Background/Objectives: The aim was to investigate the short-term outcomes of three consecutive monthly aflibercept 8 mg administrations for treatment-naïve eyes with exudative age-related macular degeneration (AMD). Methods: Twenty-one eyes with exudative AMD were included (type 1 macular neovascularization: eleven eyes; type 2 macular neovascularization, four eyes; and polypoidal choroidal vasculopathy (PCV), six eyes). All eyes received three consecutive monthly administrations of aflibercept 8 mg (114.3 mg/mL) at an injection volume of 0.07 mL. Indocyanine green angiography (ICGA) was performed on eyes with PCV at baseline and at the 3-month visit. Results: The best-corrected visual acuity significantly (BCVA) improved from 0.31 ± 0.38 (baseline) to 0.25 ± 0.38 at the 3-month visits (p = 0.035). Dry macula achieved 62% and 100% at the 1-month and 3-month visits, respectively. Central retinal thickness and subfoveal choroidal thickness significantly decreased by 55.7% and 19.8%, from 341 ± 112 (baseline) to 190 ± 64 (3-month visits) and from 192 ± 50 (baseline) to 154 ± 51 (3-month visits), respectively (both p < 0.001). Complete regression of polypoidal lesions was seen in five (83.3%) eyes out of six on ICGA at the 3-month visit. No systemic adverse events were noted, and one eye developed a retinal pigment epithelial tear one month after the first injection. Conclusions: Three consecutive monthly administrations of aflibercept (8 mg) were safe and effective for resolving exudation and polyp regression, with significant BCVA improvement in treatment-naïve eyes with exudative AMD. Full article
(This article belongs to the Special Issue Pharmacotherapy for Macular Diseases 2024)
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19 pages, 483 KiB  
Systematic Review
Omalizumab and Oral Immunotherapy in IgE-Mediated Food Allergy in Children: A Systematic Review and a Meta-Analysis
by Enrico Vito Buono, Giuliana Giannì, Sara Scavone, Susanna Esposito and Carlo Caffarelli
Pharmaceuticals 2025, 18(3), 437; https://doi.org/10.3390/ph18030437 - 20 Mar 2025
Cited by 1 | Viewed by 595
Abstract
Background: Food allergies are a growing global health concern, particularly among children, with no widely approved curative treatment beyond strict allergen avoidance. Oral immunotherapy (OIT) has emerged as a promising strategy to induce desensitization, yet its implementation is limited due to high rates [...] Read more.
Background: Food allergies are a growing global health concern, particularly among children, with no widely approved curative treatment beyond strict allergen avoidance. Oral immunotherapy (OIT) has emerged as a promising strategy to induce desensitization, yet its implementation is limited due to high rates of allergic reactions and patient non-compliance. Omalizumab, a monoclonal anti-IgE antibody, has been proposed as an adjunct to OIT to enhance safety and efficacy. Objective: This systematic review and meta-analysis aim to evaluate the efficacy and safety of omalizumab in combination with OIT for IgE-mediated food allergy in children. Methods: A systematic literature search was conducted in PubMed/MEDLINE and Cochrane Central databases to identify randomized controlled trials (RCTs), controlled clinical trials (CCTs), and observational studies assessing omalizumab as an adjunct to OIT in pediatric food allergy. Studies were evaluated for desensitization rates, immunological changes, adverse events, and quality-of-life improvements. Results: OIT combined with omalizumab led to significantly higher rates of desensitization, allowing patients to tolerate higher doses of allergens in a shorter timeframe compared to OIT alone. Omalizumab was associated with a reduction in adverse reactions, including anaphylaxis, and improved treatment adherence. However, the long-term sustainability of tolerance post-omalizumab discontinuation remains uncertain. Conclusions: Omalizumab facilitates rapid and effective desensitization in pediatric food allergy, enhancing the safety of OIT. Further research is needed to determine optimal treatment duration, long-term outcomes, and cost-effectiveness before widespread clinical adoption. Full article
(This article belongs to the Special Issue Pediatric Drug Therapy: Safety, Efficacy, and Personalized Medicine)
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5 pages, 177 KiB  
Editorial
Computer-Aided Drug Design and Drug Discovery
by Dragos Paul Mihai and George Mihai Nitulescu
Pharmaceuticals 2025, 18(3), 436; https://doi.org/10.3390/ph18030436 - 20 Mar 2025
Viewed by 390
Abstract
In the rapidly evolving landscape of pharmaceutical research, the integration of computational methods has become a cornerstone in drug discovery and development efforts [...] Full article
(This article belongs to the Section Medicinal Chemistry)
20 pages, 4911 KiB  
Article
Therapeutic Potential of Qilianxiaopi Formula: Targeting ADAM17-Mediated Chronic Inflammation in Atrophic Gastritis
by Sijing Du, Tianxiang Wang, Zhiqiang Li, Ting Li, Zelong Miao, Yuling Chen, Songbiao Zhu, Wei Wei and Haiteng Deng
Pharmaceuticals 2025, 18(3), 435; https://doi.org/10.3390/ph18030435 - 19 Mar 2025
Viewed by 462
Abstract
Background: Gastric cancer (GC) is a leading cause of mortality worldwide, particularly in China. Chronic atrophic gastritis (CAG) and intestinal metaplasia (IM) are recognized as precancerous conditions contributing to GC development. Qilianxiaopi formula (QLXP), a traditional Chinese medicine (TCM), has demonstrated significant [...] Read more.
Background: Gastric cancer (GC) is a leading cause of mortality worldwide, particularly in China. Chronic atrophic gastritis (CAG) and intestinal metaplasia (IM) are recognized as precancerous conditions contributing to GC development. Qilianxiaopi formula (QLXP), a traditional Chinese medicine (TCM), has demonstrated significant therapeutic effects on CAG and IM; however, its underlying mechanisms remain poorly understood. Methods: This study utilized chromatography-mass spectrometry to identify the major compounds in QLXP. Network pharmacology was used to predict the associated targets of these components. Thermal proteome profiling (TPP) pinpointed the potential binding proteins of QLXP, which were validated by bioinformatic analyses. Bio-layer interferometry (BLI) was used to analyze the interactions between QLXP and its key target proteins, thereby determining their binding components. Molecular docking predicted the binding modes between the components and proteins. Results: ADAM17 was identified as a key binding protein for QLXP. Further investigation revealed that QLXP inhibits the enzymatic activity of ADAM17, thereby reducing the secretion of the pro-inflammatory cytokine TNF-α, contributing to the anti-inflammatory properties of QLXP. BLI confirmed direct and reversible binding interactions between QLXP and ADAM17. Narirutin, isolated from the ADAM17 binding fraction, displayed the highest affinity for QLXP. Conclusions: This study highlights ADAM17 as a key molecular target of QLXP and narirutin as its principal binding component. The integrated approach combining chromatography-mass spectrometry, network pharmacology, TPP, BLI, and molecular docking provides a robust framework for elucidating the mechanisms of action of TCM. Full article
(This article belongs to the Special Issue Therapeutic Potential of Natural Products in Internal Diseases)
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12 pages, 925 KiB  
Opinion
Navigating the Development of Dry Powder for Inhalation: A CDMO Perspective
by Beatriz Noriega-Fernandes, Mariam Ibrahim, Rui Cruz, Philip J. Kuehl and Kimberly B. Shepard
Pharmaceuticals 2025, 18(3), 434; https://doi.org/10.3390/ph18030434 - 19 Mar 2025
Viewed by 660
Abstract
Interest in pulmonary/nasal routes for local delivery has significantly increased over the last decade owing to challenges faced in the delivery of molecules with poor solubility, systemic side effects, or new modalities such as biologics. This increasing interest has attracted new stakeholders to [...] Read more.
Interest in pulmonary/nasal routes for local delivery has significantly increased over the last decade owing to challenges faced in the delivery of molecules with poor solubility, systemic side effects, or new modalities such as biologics. This increasing interest has attracted new stakeholders to the field who have yet to explore inhaled drug product development. Contract development and manufacturing organizations (CDMOs) play a key role in supporting the development of drug products for inhalation, from early feasibility to post marketing. However, a critical gap exists for these newcomers: a clear, integrated, and a CDMO-centric roadmap for navigating the complexities of pulmonary/nasal drug product development. The purpose of this publication is to highlight the key aspects considered in the product development of inhaled dry powder products from a CDMO perspective, providing a novel and stepwise development strategy. A roadmap for the development of inhalable drug products is proposed with authors’ recommendations to facilitate the decision-making process, starting from the definition of the desired target product profile followed by dose selection in preclinical studies. The importance of understanding the nature of the API, whether a small molecule or a biologic, will be highlighted. Additionally, technical guidance on the choice of formulation (dry powder/liquid) will be provided with special focus on dry powders. Selection criteria for the particle engineering technology, mainly jet milling and spray drying, will also be discussed, including the advantages and limitations of such technologies, based on the authors’ industry expertise. Lastly, the paper will highlight the challenges and considerations for encapsulating both spray dried and jet milled powders. Unlike existing literature, this paper offers a unified framework that bridges preclinical, formulation, manufacturing, and encapsulation considerations, providing a practical tool for newcomers. Full article
(This article belongs to the Special Issue Emerging Trends in Inhaled Drug Delivery)
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22 pages, 23034 KiB  
Article
Mechanistic Insights into the Anticancer Potential of Asparagus racemosus Willd. Against Triple-Negative Breast Cancer: A Network Pharmacology and Experimental Validation Study
by Arif Jamal Siddiqui, Salem Elkahoui, Ahmed Mohajja Alshammari, Mitesh Patel, Ahmed Eisa Mahmoud Ghoniem, Randa Abdeen Husien Abdalla, Hemlata Dwivedi-Agnihotri, Riadh Badraoui and Mohd Adnan
Pharmaceuticals 2025, 18(3), 433; https://doi.org/10.3390/ph18030433 - 19 Mar 2025
Viewed by 454
Abstract
Background/Objectives: The present study investigated the anticancer potential of Asparagus racemosus Willd. against triple-negative breast cancer (TNBC) using a combined in silico and in vitro approach. Methods: Network pharmacology identified 115 potential targets shared between A. racemosus phytochemicals and TNBC, highlighting [...] Read more.
Background/Objectives: The present study investigated the anticancer potential of Asparagus racemosus Willd. against triple-negative breast cancer (TNBC) using a combined in silico and in vitro approach. Methods: Network pharmacology identified 115 potential targets shared between A. racemosus phytochemicals and TNBC, highlighting key cancer-related pathways. Molecular docking predicted strong binding affinities between specific phytochemicals (beta-sitosterol, quercetin, and others) and crucial TNBC targets, including AKT1 and ERBB2. Results: Molecular dynamics simulations validated these interactions, demonstrating stable complex formation. In vitro, A. racemosus crude extracts exhibited potent anticancer activity against MDA-MB-231 TNBC cells, showing a dose-dependent reduction in viability (IC50 = 90.44 μg/mL), induction of G1 phase cell cycle arrest, and significant early apoptosis. Conclusions: These integrated findings provide compelling evidence for the anticancer potential of A. racemosus against TNBC, suggesting its promise for further development as a therapeutic strategy. Full article
(This article belongs to the Special Issue Exploring Natural Products with Antioxidant and Anticancer Properties)
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21 pages, 905 KiB  
Review
Phenotyping the Use of Cangrelor in Percutaneous Coronary Interventions
by Nikolaos Pyrpyris, Kyriakos Dimitriadis, Konstantinos G. Kyriakoulis, Stergios Soulaidopoulos, Panagiotis Tsioufis, Aggelos Papanikolaou, Nikolaos G. Baikoussis, Alexios Antonopoulos, Konstantinos Aznaouridis and Konstantinos Tsioufis
Pharmaceuticals 2025, 18(3), 432; https://doi.org/10.3390/ph18030432 - 19 Mar 2025
Viewed by 373
Abstract
The use of antiplatelet agents is essential in percutaneous coronary interventions, both periprocedurally and in the post-interventional period. Procedural antiplatelet therapy, aiming to limit ischemic complications, is mostly administered with oral agents, including aspirin and P2Y12 inhibitors. However, there are several limitations in [...] Read more.
The use of antiplatelet agents is essential in percutaneous coronary interventions, both periprocedurally and in the post-interventional period. Procedural antiplatelet therapy, aiming to limit ischemic complications, is mostly administered with oral agents, including aspirin and P2Y12 inhibitors. However, there are several limitations in the use of oral P2Y12 inhibitors, including their difficult administration in patients presenting with cardiogenic shock and their relatively slower onset of action, leaving a significant period of the procedure with a suboptimal antiplatelet effect. These pitfalls could be avoided with the use of cangrelor, the only available intravenous P2Y12 inhibitor, which has a rapid onset and offset antiplatelet effect, as well as a favorable pharmacological profile. The use of cangrelor has been increasing in recent years, with several studies aiming to determine what the optimal patient phenotype to receive such treatment ultimately is and how its use could be adjunctive to oral P2Y12 inhibitors. Therefore, the aim of this review is to provide an overview of the pharmacological profile of cangrelor and an update regarding the clinical evidence supporting its use, as well as to discuss the optimal patient phenotype, related clinical algorithms, and future implications for larger implementation of this agent into everyday clinical practice. Full article
(This article belongs to the Special Issue Smooth Muscle and Endothelial Cells as Pharmacological Targets for Acute Oxidative Stress)
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29 pages, 6589 KiB  
Article
Identification of Deregulated miRNAs and mRNAs Involved in Tumorigenesis and Detection of Glioblastoma Patients Applying Next-Generation RNA Sequencing
by Dóra Géczi, Álmos Klekner, István Balogh, András Penyige, Melinda Szilágyi, József Virga, Andrea Bakó, Bálint Nagy, Bernadett Torner and Zsuzsanna Birkó
Pharmaceuticals 2025, 18(3), 431; https://doi.org/10.3390/ph18030431 - 19 Mar 2025
Viewed by 416
Abstract
(1) Background: Glioblastoma (GBM) is one of the most aggressive brain tumors with a poor prognosis. Therefore, new insights into GBM diagnosis and treatment are required. In addition to differentially expressed mRNAs, miRNAs may have the potential to be applied as diagnostic biomarkers. [...] Read more.
(1) Background: Glioblastoma (GBM) is one of the most aggressive brain tumors with a poor prognosis. Therefore, new insights into GBM diagnosis and treatment are required. In addition to differentially expressed mRNAs, miRNAs may have the potential to be applied as diagnostic biomarkers. (2) Methods: In this study, profiling of human miRNAs in combination with mRNAs was performed on total RNA isolated from tissue samples of five control and five GBM patients, using a high-throughput RNA sequencing (RNA-Seq) approach. (3) Results: A total of 35 miRNAs and 365 mRNAs were upregulated, while 82 miRNAs and 1225 mRNAs showed significant downregulation between tissue samples of GBM patients compared to the control samples using the iDEP tool to analyze RNA-Seq data. To validate our results, the expression of five miRNAs (hsa-miR-196a-5p, hsa-miR-21-3p, hsa-miR-10b-3p, hsa-miR-383-5p, and hsa-miR-490-3p) and fourteen mRNAs (E2F2, HOXD13, VEGFA, CDC45, AURKB, HOXC10, MYBL2, FABP6, PRLHR, NEUROD6, CBLN1, HRH3, HCN1, and RELN) was determined by RT-qPCR assay. The miRNet tool was used to build miRNA–target interaction. Furthermore, a protein–protein interaction (PPI) network was created from the miRNA targets by applying the NetworkAnalyst 3.0 tool. Based on the PPI network, a functional enrichment analysis of the target proteins was also carried out. (4) Conclusions: We identified an miRNA panel and several deregulated mRNAs that could play an important role in tumor development and distinguish GBM patients from healthy controls with high sensitivity and specificity using total RNA isolated from tissue samples. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Brain Cancer: Recent Advances and Future Trends)
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38 pages, 1377 KiB  
Review
Advances in Molecular Function and Recombinant Expression of Human Collagen
by Wenli Sun, Mohamad Hesam Shahrajabian, Kun Ma and Shubin Wang
Pharmaceuticals 2025, 18(3), 430; https://doi.org/10.3390/ph18030430 - 18 Mar 2025
Viewed by 684
Abstract
Collagen is the main protein found in skin, bone, cartilage, ligaments, tendons and connective tissue, and it can exhibit properties ranging from compliant to rigid or form gradients between these states. The collagen family comprises 28 members, each containing at least one triple-helical [...] Read more.
Collagen is the main protein found in skin, bone, cartilage, ligaments, tendons and connective tissue, and it can exhibit properties ranging from compliant to rigid or form gradients between these states. The collagen family comprises 28 members, each containing at least one triple-helical domain. These proteins play critical roles in maintaining mechanical characteristics, tissue organization, and structural integrity. Collagens regulate cellular processes such as proliferation, migration, and differentiation through interactions with cell surface receptors. Fibrillar collagens, the most abundant extracellular matrix (ECM) proteins, provide organs and tissues with structural stability and connectivity. In the mammalian myocardial interstitium, types I and III collagens are predominant: collagen I is found in organs, tendons, and bones; collagen II is found in cartilage; collagen III is found in reticular fibers; collagen IV is found in basement membranes; and collagen V is found in nails and hair. Recombinant human collagens, particularly in sponge-like porous formats combined with bone morphogenetic proteins, serve as effective scaffolds for bone repair. Due to their biocompatibility and low immunogenicity, collagens are pivotal in tissue engineering applications for skin, bone, and wound regeneration. Recombinant technology enables the production of triple-helical collagens with amino acid sequences identical to human tissue-derived collagens. This review summarizes recent advances in the molecular functions and recombinant expression of human collagens, with a focus on their biomedical applications. Full article
(This article belongs to the Special Issue Biomedical Properties, Developments and Therapeutic Potential of Sesquiterpenoid Lactones and Natural Compounds)
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13 pages, 2492 KiB  
Article
Molluscicidal and Schistosomicidal Activities of 2-(1H-Pyrazol-1-yl)-1,3,4-thiadiazole Derivatives
by Leonardo da Silva Rangel, Daniel Tadeu Gomes Gonzaga, Ana Cláudia Rodrigues da Silva, Natalia Lindmar von Ranke, Carlos Rangel Rodrigues, José Augusto Albuquerque dos Santos, Nubia Boechat, Keyla Nunes Farias Gomes, Guilherme Pegas Teixeira and Robson Xavier Faria
Pharmaceuticals 2025, 18(3), 429; https://doi.org/10.3390/ph18030429 - 18 Mar 2025
Viewed by 258
Abstract
Background/objectives: Schistosomiasis is caused by flatworms of the genus Schistosoma, for which mollusks of the genus Biomphalaria are intermediate hosts. Niclosamide (NCL) is a molluscicide recommended by the World Health Organization (WHO) for control of Biomphalaria. Although effective, it is expensive [...] Read more.
Background/objectives: Schistosomiasis is caused by flatworms of the genus Schistosoma, for which mollusks of the genus Biomphalaria are intermediate hosts. Niclosamide (NCL) is a molluscicide recommended by the World Health Organization (WHO) for control of Biomphalaria. Although effective, it is expensive and environmentally toxic, which raises concerns regarding its widespread use. As a result, we explored new synthetic substances as alternative strategies for controlling Biomphalaria glabrata. We evaluated the molluscicidal activity of 2-(1H-py-razol-1-yl)-1,3,4-thiadiazole and 2-(4,5-dihydro-1H-pyrazol-1-yl)-1,3,4-thiadiazole derivatives against B. glabrata snails and embryos, as well as Schistosoma cercariae (infective larvae). Methods: Adult and young snails were added to 24-well plates containing 20 synthetic compounds from the PDAN series for initial screening over 96 h at a concentration of 100 ppm. Water and NCL (2 ppm) were used as the negative and positive controls, respectively. Active compounds in the adult B. glabrata assay were selected for the tests vs. embryos and cercariae. Results: In the initial screen, only PDAN 52 (63 ± 4%) and 79 (12 ± 3%) showed molluscicidal activity at a concentration of 100 ppm up to 48 h. Consequently, we selected only PDAN 52. The LC50 value found in the tests on embryos after 24 h of treatment was 20 ± 2 ppm and, after 48 h, it was 4 ± 0.5 ppm. Against cercariae, we measured an LC50 value of 68 ± 5 ppm after 4 h of treatment. PDAN 52 did not induce marked toxicity against a second mollusk, Physella acuta, after 48 h of exposure. Conclusions: We highlight the promising molluscicidal activity of PDAN 52 against different developmental stages of the mollusk, B. glabrata, as well the infective larvae of Schistosoma mansoni. Full article
(This article belongs to the Section Pharmacology)
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23 pages, 17368 KiB  
Article
Huafengdan Inhibits Glioblastoma Cell Growth and Mobility by Acting on PLAU and CAV1 Targets
by Dengxiao Lin, Wenfeng Yu, Jia Yu, Sha Cheng, Yu Song, Xiaoqing Wan, Yingjiang Xu, Heng Luo and Baofei Sun
Pharmaceuticals 2025, 18(3), 428; https://doi.org/10.3390/ph18030428 - 18 Mar 2025
Viewed by 280
Abstract
Background: Glioblastoma (GBM) is considered a clinically refractory malignant tumor due to its high recurrence and malignancy, invasiveness, and poor prognosis. The ethnomedicine Huafengdan (HFD) is prepared using several Chinese herbs by a complex fermentation process that has a long history. Previous [...] Read more.
Background: Glioblastoma (GBM) is considered a clinically refractory malignant tumor due to its high recurrence and malignancy, invasiveness, and poor prognosis. The ethnomedicine Huafengdan (HFD) is prepared using several Chinese herbs by a complex fermentation process that has a long history. Previous studies have reported the inhibitory effect of HFD on GBM both in vitro and in vivo; however, its mechanism of action is unclear. Methods: The inhibitory effects of HFD on the growth, migration, and invasion of GBM cells were determined using the MTT assay, EdU assay, Transwell assay, flow cytometry, and Western blotting. A subcutaneous graft tumor model of nude BALB/c mice was established using U87 cells, and the in vivo activity and toxicity of HFD were evaluated using immunohistochemical staining and hematoxylin and eosin staining. Network pharmacology, bioinformatics, and transcriptomics were used to screen the targets and related signaling pathways of HFD in GBM and were validated using qPCR, CETSA, and Western blotting. Results: HFD inhibited the proliferation, invasion, and migration of GBM cells and induced S-phase block and apoptosis in GBM cells. It inhibited the in vivo growth of GBM cells without obvious toxicity. Mechanistic studies showed that the inhibition of GBM cell growth, migration, and invasion by HFD involved the key targets PLAU and CAV1. Its associated signaling pathways were the PI3K/Akt signaling pathway and cell cycle signaling pathway. Conclusions: Our findings confirm the novel function of HFD in inhibiting GBM cell growth in vitro and in vivo and highlight its potential in treating GBM. Full article
(This article belongs to the Section Pharmacology)
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18 pages, 2275 KiB  
Article
In Vitro Efficacy and Toxicity Assessment of an Amphotericin B Gel for the Treatment of Cutaneous Leishmaniasis
by Lilian Sosa, Lupe Carolina Espinoza, Marcelle Silva-Abreu, Ximena Jaramillo-Fierro, Diana Berenguer, Cristina Riera, María Rincón and Ana C. Calpena
Pharmaceuticals 2025, 18(3), 427; https://doi.org/10.3390/ph18030427 - 18 Mar 2025
Viewed by 311
Abstract
Background/Objectives: Leishmaniasis is a neglected tropical disease caused by a protozoan parasite of Leishmania. This study aimed to evaluate the in vitro efficacy and toxicity of a previously developed amphotericin gel as a possible treatment for cutaneous leishmaniasis. Methods: First, [...] Read more.
Background/Objectives: Leishmaniasis is a neglected tropical disease caused by a protozoan parasite of Leishmania. This study aimed to evaluate the in vitro efficacy and toxicity of a previously developed amphotericin gel as a possible treatment for cutaneous leishmaniasis. Methods: First, quality control of the AmB-gel was carried out, including microbiological stability. The permeated and retained drug was tested on healthy and lacerated human skin. Tolerance to the AmB-gel was tested in vitro using HaCaT, RAW 264.7, and J774 cell lines and by an irritation test (HET-CAM). Promastigotes and amastigotes of various Leishmania species were tested, and the microscopic morphology of promastigotes exposed to the formulation was analyzed. Computational analysis was performed on the drug, polymer, and ergosterol in the promastigote. Results: The AmB-gel presented appropriate characteristics for topical use, including no microbial contamination after storage. The amount of drug retained on the intact and injured skin was 1180.00 ± 13.54 µg/g/cm2 and 750.18 ± 5.43 µg/g/cm2, respectively. The AmB-gel did not cause significant signs of toxicity. The IC50 of the AmB-gel for promastigotes was less than 1 µg/mL for the four species examined, i.e., Leishmania infantum, Leishmania tropica, Leishmania major, and Leishmania braziliensis, and less than 2 µg/mL for amastigotes of Leishmania infantum and Leishmania tropica. The AmB-gel caused notable effects on the surface of promastigotes. Computational analysis revealed primarily hydrophobic and van der Waals interactions between AmB and Pluronic® F127 and ergosterol. Conclusions: Based on the drug retention content and IC50 values observed for both parasite stages, the AmB-gel may be a promising candidate for in vivo studies in patients with cutaneous leishmaniasis. Full article
(This article belongs to the Section Pharmaceutical Technology)
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27 pages, 7159 KiB  
Article
Wuzhuyu Decoction Relieves Chronic Migraine by Regulating 5-HT1A and 3A Receptors-Mediated CREB Signaling Pathway in Brain and Intestine
by Zhimin Song, Meijing Li, Ziwei Zhou, Xiaomeng Guo, Qi Wang, Zekuan Zhang, Keshu Wang, Qixiang Zheng, Wenjing Gou, Sha Wu, Hui Zhao and Muxin Gong
Pharmaceuticals 2025, 18(3), 426; https://doi.org/10.3390/ph18030426 - 18 Mar 2025
Viewed by 322
Abstract
Background: Chronic migraine (CM) is a common complex nervous system disease, often accompanied by symptoms of the digestive tract that interact with each other, leading to prolonged and difficult-to-cure migraines. These symptoms are associated with abnormalities in 5-HT and its receptors. Wuzhuyu decoction [...] Read more.
Background: Chronic migraine (CM) is a common complex nervous system disease, often accompanied by symptoms of the digestive tract that interact with each other, leading to prolonged and difficult-to-cure migraines. These symptoms are associated with abnormalities in 5-HT and its receptors. Wuzhuyu decoction (WZYD) is a traditional Chinese medicine prescription commonly used in clinics to treat CM; it relieves gastrointestinal symptoms, such as nausea and vomiting; however, its mechanism is still unclear. Investigating the differences in the role of WZYD compared to existing drugs targeting 5-HT receptors in the treatment of CM not only helps elucidate its pathogenesis but also provides possibilities for the development of new therapeutic approaches. Methods: An inflammation soup (IS)-induced CM male rat model was established. Based on a preliminary experiment, the target of WZYD in treating CM was determined by network pharmacology, and verified by molecular docking. ELISA, immunofluorescence, western blot, and real-time quantitative polymerase chain reaction (RT-qPCR) were used to evaluate the expression levels of CM-related indicators (5-HT, calcitonin gene-related peptide (CGRP), and c-Fos) to ensure the successful establishment of the CM model and the effectiveness of the drug. On this basis, the protein expression levels of 5-HT1A/3A receptors and their cAMP-response element binding protein (CREB) signaling pathway were detected by western blot and immunohistochemistry. The role of 5-HT1A/3A receptors in the treatment of CM by WZYD was validated using a 5-HT1A receptor antagonist (WAY 100635) and a 5-HT3A receptor agonist (SR 57227). Results: The results showed that WZYD increased the expression of 5-HT in the brain, decreased the expression of CGRP, c-Fos, ionized calcium-binding adapter molecule 1 (Iba1), and relieved CM. At the same time, WZYD also increased the expression of the 5-HT1A receptor and decreased the expression of the 5-HT3A receptor in the brain and colon of CM rats. Subsequently, WZYD further exerted its brain-gut integrated therapeutic effects by regulating the CREB signaling pathway mediated by 5-HT1A/3A receptors in the brain and colon of CM rats. Conclusions: WZYD not only regulates neurotransmitters in the brain and colon at the same time, but also specifically regulates 5-HT1A/3A receptors in the brain and colon, which explains the characteristics and advantages of WZYD from a new perspective. While effectively relieving headache symptoms, it also improves related gastrointestinal symptoms, which is more conducive to the treatment of CM. Full article
(This article belongs to the Section Pharmacology)
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17 pages, 2643 KiB  
Article
Physiologically Based Pharmacokinetic Modeling of Tofacitinib: Predicting Drug Exposure and Optimizing Dosage in Special Populations and Drug–Drug Interaction Scenarios
by Zhihai Cao, Zilong Wang, Qian Zhang, Wei Zhang, Liang Zheng and Wei Hu
Pharmaceuticals 2025, 18(3), 425; https://doi.org/10.3390/ph18030425 - 18 Mar 2025
Viewed by 324
Abstract
Background: Tofacitinib is mainly used in the adult population for immune-mediated inflammatory diseases. There is little information available on the pharmacokinetics of tofacitinib in pediatric patients, populations with hepatic impairment and renal impairment, and patients with drug–drug interactions (DDIs). This study aimed to [...] Read more.
Background: Tofacitinib is mainly used in the adult population for immune-mediated inflammatory diseases. There is little information available on the pharmacokinetics of tofacitinib in pediatric patients, populations with hepatic impairment and renal impairment, and patients with drug–drug interactions (DDIs). This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of tofacitinib in the populations mentioned above. Methods: We developed the PBPK models in PK-Sim® and evaluated the models with observed clinical PK data. The Monte Carlo algorithm was used for parameter identification. Results: The adult PBPK model accurately simulated the pharmacokinetic profiles of all administration scenarios. The geometric mean fold errors for the predicted/observed maximum concentration and area under the curve are 1.17 and 1.16, respectively. The extrapolated models accurately simulated the pharmacokinetic characteristics of tofacitinib. The pediatric patients aged 12-to-<18 years and 2-to-<6 years need to adjust the dose to 4 mg BID and 1.7 mg BID, respectively, to achieve comparable steady-state exposures to 5 mg BID in adults. The populations with moderate hepatic impairment and severe renal impairment need to reduce the dose to 50% and 75% of the original dose, respectively. Tofacitinib should be reduced to 50% and 65% of the original dose for concomitant use with fluconazole and ketoconazole, respectively, and increased to 150% of the original dose for concomitant use with rifampicin. Conclusions: We developed a tofacitinib PBPK model and extrapolated it to special populations and DDIs. The predictive results of the models can help the rational use of tofacitinib in these populations. Full article
(This article belongs to the Section Pharmacology)
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28 pages, 1825 KiB  
Review
The Importance of Murine Models in Determining In Vivo Pharmacokinetics, Safety, and Efficacy in Antimalarial Drug Discovery
by Glory Adebayo, Opeyemi I. Ayanda, Matthias Rottmann, Olusola S. Ajibaye, Gbolahan Oduselu, Julius Mulindwa, Olayinka O. Ajani, Oluwagbemiga Aina, Pascal Mäser and Ezekiel Adebiyi
Pharmaceuticals 2025, 18(3), 424; https://doi.org/10.3390/ph18030424 - 18 Mar 2025
Viewed by 607
Abstract
New chemical entities are constantly being investigated towards antimalarial drug discovery, and they require animal models for toxicity and efficacy testing. Murine models show physiological similarities to humans and are therefore indispensable in the search for novel antimalarial drugs. They provide a preclinical [...] Read more.
New chemical entities are constantly being investigated towards antimalarial drug discovery, and they require animal models for toxicity and efficacy testing. Murine models show physiological similarities to humans and are therefore indispensable in the search for novel antimalarial drugs. They provide a preclinical basis (following in vitro assessments of newly identified lead compounds) for further assessment in the drug development pipeline. Specific mouse strains, non-humanized and humanized, have successfully been infected with rodent Plasmodium species and the human Plasmodium species, respectively. Infected mice provide a platform for the assessment of treatment options being sought. In vivo pharmacokinetic evaluations are necessary when determining the fate of potential antimalarials in addition to the efficacy assessment of these chemical entities. This review describes the role of murine models in the drug development pipeline. It also explains some in vivo pharmacokinetic, safety, and efficacy parameters necessary for making appropriate choices of lead compounds in antimalarial drug discovery. Despite the advantages of murine models in antimalarial drug discovery, certain limitations are also highlighted. Full article
(This article belongs to the Special Issue Antimalarial Drug Candidates)
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18 pages, 1706 KiB  
Article
Development of a Medication-Related Osteonecrosis of the Jaw Prediction Model Using the FDA Adverse Event Reporting System Database and Machine Learning
by Shinya Toriumi, Komei Shimokawa, Munehiro Yamamoto and Yoshihiro Uesawa
Pharmaceuticals 2025, 18(3), 423; https://doi.org/10.3390/ph18030423 - 17 Mar 2025
Cited by 1 | Viewed by 471
Abstract
Background: Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse event. Herein, we conducted a quantitative structure–activity relationship analysis using the U.S. Food and Drug Administration Adverse Drug Reaction Database System (FAERS) and machine learning to construct a drug prediction [...] Read more.
Background: Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse event. Herein, we conducted a quantitative structure–activity relationship analysis using the U.S. Food and Drug Administration Adverse Drug Reaction Database System (FAERS) and machine learning to construct a drug prediction model for MRONJ induction based solely on chemical structure information. Methods: A total of 4815 drugs from FAERS were evaluated, including 70 and 139 MRONJ-positive and MRONJ-negative drugs, respectively, identified based on reporting odds ratios, Fisher’s exact tests, and ≥100 total adverse event reports. Then, we calculated 326 chemical structure descriptors for each drug and compared three supervised learning algorithms (random forest, gradient boosting, and artificial neural networks). We also compared the number of chemical structure descriptors (5, 6, 7, 8, 9, 10, 20, and 30 descriptors). Results: We indicated that the MRONJ prediction model using an artificial neural network algorithm and eight descriptors achieved the highest validation receiver operating characteristic curve value of 0.778. Notably, the total polar surface area (ASA_P) was among the top-ranking descriptors, and MRONJ-positive drugs such as bisphosphonates and anticancer drugs showed high values. Our final model demonstrated a balanced accuracy of 0.693 and a specificity of 0.852. Conclusions: In this study, our MRONJ-inducing drug prediction model identified drugs with polar surface area properties as potential causes of MRONJ. This study demonstrates a promising approach for predicting MRONJ risk, which could enhance drug safety assessment and streamline drug screening in clinical and preclinical settings. Full article
(This article belongs to the Special Issue Bone Disorder Therapeutics: Novel Drug Candidates and Treatment Strategies)
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19 pages, 1214 KiB  
Review
Vatairea Genus as a Potential Therapeutic Agent—A Comprehensive Review of Ethnobotanical, Phytochemical, and Pharmacological Properties
by Sarah Andrade Toledo, Laryssa Danielle da Silva Reis, Brenda Costa da Conceição, Lucas Villar Pedrosa da Silva Pantoja, Fábio José Coelho de Souza-Junior, Flávia Cristina Santos Garcez, Cristiane Socorro Ferraz Maia and Eneas Andrade Fontes-Junior
Pharmaceuticals 2025, 18(3), 422; https://doi.org/10.3390/ph18030422 - 17 Mar 2025
Viewed by 349
Abstract
The Vatairea genus (Fabaceae family) is widespread in the Amazon rainforest. Some species of this genus are known for their ethnobotanical significance and biological potential. The present study explores the pharmacological and promising therapeutic activities, ethnobotanical profile, and phytochemical prospection of Vatairea sp., [...] Read more.
The Vatairea genus (Fabaceae family) is widespread in the Amazon rainforest. Some species of this genus are known for their ethnobotanical significance and biological potential. The present study explores the pharmacological and promising therapeutic activities, ethnobotanical profile, and phytochemical prospection of Vatairea sp., a monophyletic group of flowering plants, which includes economically and culturally important genera due to their diverse uses, including medicinal applications. V. lundellii, V. guianensis, V. erythrocarpa, V. fusca, V. heteroptera, V. paraensis, V. sericea, and V. macrocarpa are included in the Vatairea sp., also recognized for its high wood quality and potential medicinal properties. Studies show significant antibacterial activity in V. guianensis extracts against Gram-positive and Gram-negative bacteria, whereas V. macrocarpa lectin exhibits broad-spectrum antibacterial effects, including modulation of antibiotic resistance. Additionally, V. macrocarpa and V. guianensis have demonstrated antifungal properties, with compounds like Vatacarpan exhibiting potent activity against Candida sp. In vivo studies highlight the neurotoxic effects of V. macrocarpa lectin, suggesting a dual role in the central nervous system. Despite these findings, research on Vatairea’s toxicological aspects is limited, with only a few studies on V. macrocarpa and V. guianensis extracts indicating a need for further exploration of this genus’ pharmacological and therapeutic potential. Full article
(This article belongs to the Special Issue Therapeutic Potential of Natural Products in Internal Diseases)
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40 pages, 9219 KiB  
Article
Enhanced Intranasal Delivery of Atorvastatin via Superparamagnetic Iron-Oxide-Loaded Nanocarriers: Cytotoxicity and Inflammation Evaluation and In Vivo, In Silico, and Network Pharmacology Study for Targeting Glioblastoma Management
by Kristina Zarif Attalla, Doaa H. Hassan, Mahmoud H. Teaima, Carol Yousry, Mohamed A. El-Nabarawi, Mohamed A. Said and Sammar Fathy Elhabal
Pharmaceuticals 2025, 18(3), 421; https://doi.org/10.3390/ph18030421 - 16 Mar 2025
Viewed by 426
Abstract
Objective: This study aims to develop an intranasal (IN) delivery system for glioblastoma multiforme (GBM) management using repurposed superparamagnetic iron-oxide (SPION) loaded with atorvastatin (ATO)-nanostructured lipid carrier (NLC). Methods: Emulsification and ultrasonication were used to formulate ATO-NLCs, and the best formula [...] Read more.
Objective: This study aims to develop an intranasal (IN) delivery system for glioblastoma multiforme (GBM) management using repurposed superparamagnetic iron-oxide (SPION) loaded with atorvastatin (ATO)-nanostructured lipid carrier (NLC). Methods: Emulsification and ultrasonication were used to formulate ATO-NLCs, and the best formula was loaded with SPION to make the final atorvastatin/superparamagnetic iron oxide-loaded nanostructured lipid carrier (ASN) formulation. Entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), and drug release after 6 h (Q6h) were evaluated for NLCs. ASN was tested for cytotoxicity on T98G cancer cells, and the cell cycle was examined to determine cell death. Furthermore, the ability of the optimal formulation to suppress the levels of inflammatory biomarkers was investigated in Lipopolysaccharide (LPS)-induced inflammation. The brain-targeting behavior of IN-ASN was visualized in rabbits via confocal laser scanning microscopy (CLSM). Results: The optimum NLC exhibited a spherical shape, EE% of 84.0 ± 0.67%, PS of 282.50 ± 0.51 nm, ZP of −18.40 ± 0.15 mV, and Q6h of 89.23%. The cytotoxicity of ASN against cancer cells was 4.4-fold higher than ATO suspension, with a 1.3-fold increment in cell apoptosis. ASN showed significantly reduced pro-inflammatory biomarkers (IL-β, IL-6, TNF-α, TLR4, NF-қB), whereas CLSM revealed enhanced brain delivery with no observed histopathological nasal irritation. The in silico analysis demonstrated enhanced ATO-ADME (absorption, distribution, metabolism, and excretion) properties, while the network pharmacology study identified 10 target GBM genes, among which MAPK3 was the most prominent with a good binding score as elucidated by the simulated docking study. Conclusions: These findings may present ATO/SPION-NLCs as significant evidence for repurposing atorvastatin in the treatment of glioblastoma multiforme. Full article
(This article belongs to the Special Issue Tumor Therapy and Drug Delivery)
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33 pages, 6221 KiB  
Review
Unraveling the Neuropharmacological Properties of Lippia alba: A Scientometric Approach
by Pedro I. C. Silva, Lucas V. P. S. Pantoja, Brenda C. Conceição, Marta E. O. Barbosa, Luiza F. R. Soares, Rui Daniel Prediger, Enéas A. Fontes-Júnior, Jofre J. S. Freitas and Cristiane S. F. Maia
Pharmaceuticals 2025, 18(3), 420; https://doi.org/10.3390/ph18030420 - 16 Mar 2025
Viewed by 333
Abstract
Lippia alba (Verbenaceae) is popularly known as lemon balm or false melissa and is one of the most widely used plants in traditional medicine in the Amazon region. In this study, we conducted a comprehensive bibliometric analysis, with conventional metrics associated with a [...] Read more.
Lippia alba (Verbenaceae) is popularly known as lemon balm or false melissa and is one of the most widely used plants in traditional medicine in the Amazon region. In this study, we conducted a comprehensive bibliometric analysis, with conventional metrics associated with a critical review based on the neuropharmacological activities, to identify potential medical applications and also gaps in knowledge that require further investigation. Fifty-two articles were included according to the eligibility criteria. In the country analysis, Brazil emerged as the main contributor to research with the highest number of publications and citations. Notably, nine of the ten main research institutions are Brazilian, with the Universidade Federal de Santa Maria standing out with 761 citations. The keywords “anesthesia”, “Lippia alba”, and “essential oil” were the most frequent, highlighting their importance in this field. Essential oils are the most common type of extraction, which linalool, citral, geraniol, carvone, and limonene were the main constituents identified. According to the type of study, preclinical studies presented the highest frequency, primarily through fish experimental models. The main neuropharmacological activities identified were sedative–anesthetic, anxiolytic, anticonvulsant, and analgesic, with mechanisms of action via the GABAergic pathway. This bibliometric review provided new evidence reinforcing the potential of L. alba as a promising alternative for the treatment of neuropsychiatric disorders. It also highlighted existing knowledge gaps, mainly related to the comparison of the actions of the different chemotypes of the species and the investigation of the mechanisms underlying their neuropharmacological properties. Additionally, there is a lack of knowledge in other emerging areas related to the central nervous system, such as mood and cognitive disorders. Full article
(This article belongs to the Section Natural Products)
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30 pages, 6699 KiB  
Review
Potential Benefits of In Silico Methods: A Promising Alternative in Natural Compound’s Drug Discovery and Repurposing for HBV Therapy
by Samuel Chima Ugbaja, Aganze Gloire-Aimé Mushebenge, Hezekiel Kumalo, Mlungisi Ngcobo and Nceba Gqaleni
Pharmaceuticals 2025, 18(3), 419; https://doi.org/10.3390/ph18030419 - 16 Mar 2025
Viewed by 735
Abstract
Hepatitis B virus (HBV) is an important global public health issue. The World Health Organization (WHO) 2024 Global Hepatitis Report estimated that the global prevalence of people living with HBV infection is 254 million, with an estimated prevalence incidence of 1.2 million new [...] Read more.
Hepatitis B virus (HBV) is an important global public health issue. The World Health Organization (WHO) 2024 Global Hepatitis Report estimated that the global prevalence of people living with HBV infection is 254 million, with an estimated prevalence incidence of 1.2 million new HBV infections yearly. Previous studies have shown that natural compounds have antiviral inhibition potentials. In silico methods such as molecular docking, virtual screening, pharmacophore modeling, quantitative structure–activity relationship (QSAR), and molecular dynamic simulations have been successfully applied in identifying bioactive compounds with strong binding energies in HBV treatment targets. The COVID-19 pandemic necessitated the importance of repurposing already approved drugs using in silico methods. This study is aimed at unveiling the benefits of in silico techniques as a potential alternative in natural compounds’ drug discovery and repurposing for HBV therapy. Relevant articles from PubMed, Google Scholar, and Web of Science were retrieved and analyzed. Furthermore, this study comprehensively reviewed the literature containing identified bioactive compounds with strong inhibition of essential HBV proteins. Notably, hesperidin, quercetin, kaempferol, myricetin, and flavonoids have shown strong binding energies for hepatitis B surface antigen (HBsAg). The investigation reveals that in silico drug discovery methods offer an understanding of the mechanisms of action, reveal previously overlooked viral targets (including PreS1 Domain of HBsAg and cccDNA (Covalently Closed Circular DNA) regulators, and facilitate the creation of specific inhibitors. The integration of in silico, in vitro, and in vivo techniques is essential for the discovery of new drugs for HBV therapy. The insights further highlight the importance of natural compounds and in silico methods as targets in drug discovery for HBV therapy. Moreover, the combination of natural compounds, an in silico approach, and drug repurposing improves the chances of personalized and precision medicine in HBV treatment. Therefore, we recommend drug repurposing strategies that combine in vitro, in vivo, and in silico approaches to facilitate the discovery of effective HBV drugs. Full article
(This article belongs to the Section Natural Products)
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20 pages, 3460 KiB  
Article
Discovering New Tyrosinase Inhibitors by Using In Silico Modelling, Molecular Docking, and Molecular Dynamics
by Kevin A. OréMaldonado, Sebastián A. Cuesta, José R. Mora, Marcos A. Loroño and José L. Paz
Pharmaceuticals 2025, 18(3), 418; https://doi.org/10.3390/ph18030418 - 16 Mar 2025
Viewed by 635
Abstract
Background/Objectives: This study was used in silico modelling to search for potential tyrosinase protein inhibitors from a database of different core structures for IC50 prediction. Methods: Four machine learning algorithms and topographical descriptors were tested for model construction. Results: A [...] Read more.
Background/Objectives: This study was used in silico modelling to search for potential tyrosinase protein inhibitors from a database of different core structures for IC50 prediction. Methods: Four machine learning algorithms and topographical descriptors were tested for model construction. Results: A model based on multiple linear regression was the most robust, with only six descriptors, and validated by the Tropsha test with statistical parameters R2 = 0.8687, Q2LOO = 0.8030, and Q2ext = 0.9151. From the screening of FDA-approved drugs and natural products, the pIC50 values for 15,424 structures were calculated. The applicability domain analysis covered 100% of the external dataset and 71.22% and 73.26% of the two screening datasets. Fifteen candidates with pIC50 above 7.6 were identified, with five structures proposed as potential tyrosinase enzyme inhibitors, which underwent ADME analysis. Conclusions: The molecular docking analysis was performed for the dataset used in the training-test process and for the fifteen structures from the screening dataset with potential pharmaceutical tyrosinase inhibition, followed by molecular dynamics studies for the top five candidates with the highest predicted pIC50 values. The new use of these five candidates in tyrosinase inhibition is highlighted based on their promising application in melanoma treatment. Full article
(This article belongs to the Section Medicinal Chemistry)
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18 pages, 2309 KiB  
Article
Assessing the Antibacterial Potential and Biofilm Inhibition Capability of Atorvastatin-Loaded Nanostructured Lipid Carriers via Crystal Violet Assay
by Njoud Altuwaijri, Rawan Fitaihi, Fai A. Alkathiri, Sarah I. Bukhari, Alanoud M. Altalal, Alyaa Alsalhi, Lama Alsulaiman, Aljawhara O. Alomran, Noura S. Aldosari, Safa A. Alqhafi, Majd Alhamdan and Rihaf Alfaraj
Pharmaceuticals 2025, 18(3), 417; https://doi.org/10.3390/ph18030417 - 15 Mar 2025
Viewed by 625
Abstract
Background/Objectives: Atorvastatin (ATR), an antihyperlipidemic drug with a potential antibacterial effect, was investigated in this study. Like other statins, ATR has been repurposed for several uses, ranging from anti-inflammatory to antimicrobial applications, and has demonstrated successful results. However, the efficacy of ATR [...] Read more.
Background/Objectives: Atorvastatin (ATR), an antihyperlipidemic drug with a potential antibacterial effect, was investigated in this study. Like other statins, ATR has been repurposed for several uses, ranging from anti-inflammatory to antimicrobial applications, and has demonstrated successful results. However, the efficacy of ATR is limited by its low solubility, indicating an opportunity for its encapsulation in a nanotechnology-based drug delivery system. Methods: Nanostructured lipid carrier (NLC) formulations were prepared using high-pressure homogenization and ultrasonication. The formulations were characterized, including their particle size, polydispersity index, zeta potential, encapsulation efficiency, and in vitro release. Antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli (E. coli), and Staphylococcus aureus (S. aureus) was evaluated using the growth curve (bacterial growth over time) and well diffusion methods (zone of inhibition and minimum inhibitory concentration (MIC) determination). The crystal violet assay was employed to assess biofilm inhibition. Results: The NLC formulations were optimized, and the size and zeta potential of the blank nanoparticles were 130 ± 8.39 nm and −35 ± 0.5 mV, respectively. In comparison, the encapsulated NLCs had a size of 142 ± 52.20 nm and a zeta potential of −31 ± 1.41 mV. The average encapsulation efficiency was 94%, and 70% of the drug was released after 24 h. The ATR-loaded NLCs showed significantly enhanced antibacterial activity by reducing the minimum inhibitory concentration by 2.5-fold for E. coli, 1.8-fold for S. aureus, and 1.4-fold for MRSA, and promoting more effective bacterial growth inhibition. Notably, biofilm inhibition was significantly improved with ATR-NLCs, achieving 80% inhibition for S. aureus, 40% for E. coli, and 30% for MRSA, compared to free ATR (p < 0.001). These findings suggest that NLC encapsulation enhances ATR’s antimicrobial efficacy and biofilm suppression. Conclusions: This study identified NLCs as successful carriers of ATR, significantly enhancing its antibacterial efficacy and biofilm inhibition capabilities. This formulation, which shows antimicrobial potential against both Gram-positive and Gram-negative bacteria, should be further studied and developed against different resistant microbial strains. Full article
(This article belongs to the Section Pharmaceutical Technology)
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17 pages, 1870 KiB  
Article
Mixture Containing 5% Polysaccharide Extract of Cerioporus squamosus (Huds.) Quélet, 5% Dexpanthenol, and 0.2% Hyaluronic Acid Shows In Vitro and In Vivo Wound Healing Properties
by Jovana D. Petrović, Tamara A. Carević Milićević, Jasmina M. Glamočlija, Jelena B. Kulaš and Ivana I. Mirkov
Pharmaceuticals 2025, 18(3), 416; https://doi.org/10.3390/ph18030416 - 15 Mar 2025
Viewed by 584
Abstract
Background: This study explores wound healing and the antimicrobial potential of a natural formulation containing a polysaccharide extract from Cerioporus squamosus, hyaluronic acid, and dexpanthenol. Methods: Wound healing effects were assessed using HaCaT keratinocytes, while antimicrobial activity was evaluated against human skin [...] Read more.
Background: This study explores wound healing and the antimicrobial potential of a natural formulation containing a polysaccharide extract from Cerioporus squamosus, hyaluronic acid, and dexpanthenol. Methods: Wound healing effects were assessed using HaCaT keratinocytes, while antimicrobial activity was evaluated against human skin pathogens using a microdilution assay. In vitro cytotoxicity tests ensured formulation safety, whereas in vivo wound healing was further investigated using an animal model. Gene expression analysis was performed to assess the molecular mechanisms involved. Results: The unique glucan composition of C. squamosus (15.38% α-glucans and 7.91% β-glucans) deviated from typical mushroom polysaccharide profiles, warranting further exploration of its bioactivity. In vitro mushroom polysaccharides promoted 25.35% wound closure after 24 hours, while the three-component formulation achieved 35.81% closure. Antibacterial activity showed a minimum inhibitory concentration (MIC) of 0.44–1.75 mg/mL and minimum bactericidal concentration (MBCs) of 0.88–3.50 mg/mL, while antifungal activity ranged from 0.22 to 0.44 mg/mL (MICs) and 0.44 to 0.88 mg/mL (minimum fungicidal concentration—MFC). In vivo data showed that 60% of treated wounds fully closed by day 11, despite no statistically significant difference from the control. However, gene expression analysis highlighted VEGF and collagen upregulation, indicating an enhancement of wound healing on a molecular level. Conclusions: The novel three-component formulation demonstrated consistent wound healing and antimicrobial properties, supporting its potential as a safe and effective treatment for chronic and acute wounds. Full article
(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant-Based Pharmaceuticals—4th Edition)
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23 pages, 12983 KiB  
Article
Synthesis, Molecular Simulation, DFT, and Kinetic Study of Imidazotriazole-Based Thiazolidinone as Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase Enzymes
by Manal M. Khowdiary, Shoaib Khan, Tayyiaba Iqbal, Wajid Rehman, Muhammad Bilal Khan, Mujaddad Ur Rehman, Zanib Fiaz and Hakimullah
Pharmaceuticals 2025, 18(3), 415; https://doi.org/10.3390/ph18030415 - 15 Mar 2025
Viewed by 487
Abstract
Background: Alzheimer’s disease is a complex and multifactorial brain disorder characterized by gradual memory impairment, cognitive disturbance, and severe dementia, and, ultimately, its progression leads to patient death. This research work presents the design, synthesis, and characterization of novel imidazotriazole-based thiazolidinone derivatives ( [...] Read more.
Background: Alzheimer’s disease is a complex and multifactorial brain disorder characterized by gradual memory impairment, cognitive disturbance, and severe dementia, and, ultimately, its progression leads to patient death. This research work presents the design, synthesis, and characterization of novel imidazotriazole-based thiazolidinone derivatives (1–14), displaying promising anti-Alzheimer’s activity. Methods: These derivatives were synthesized by using 1H-imidazole-2-thiol as a starting reagent. Structural characterization was accomplished by 13C-NMR and 1H-NMR, while the molecular weight was confirmed by HREI-MS. These compounds were investigated for their anti-Alzheimer’s potential under an in vitro analysis. Results: These compounds showed a significant to moderate biological potential against AChE and BChE in comparison to donepezil (IC50 = 8.50 µM and 8.90 µM against AChE and BuChE), used as a reference drug. Among these compounds, analog 10 with IC50 values of 6.70 µM and 7.10 µM against AChE and BuChE emerged as the lead compound of the series with promising biological efficacy against targeted enzymes. Molecular docking revealed the interactive nature of active ligands against target enzymes. These compounds were also assessed under dynamic conditions to examine the structural deviation and conformational changes in a protein complex structure. DFT calculations provided the relative stability and reactivity of the lead compounds. An ADMET analysis showed that these compounds have no toxicological profile. Conclusions: This research study paves the way for the further development and optimization of novel and selective imidazotriazole-based thiazolidinone inhibitors as potent anti-Alzheimer’s agents. Full article
(This article belongs to the Section Medicinal Chemistry)
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25 pages, 7183 KiB  
Article
Ceftriaxone-Loaded Liposomal Nanoparticles for Pulmonary Delivery Against Lower Respiratory Tract Infections: Development and Characterization
by Vijay Kumar Panthi, Kathryn E. Fairfull-Smith, Timothy J. Wells, Tony Wang and Nazrul Islam
Pharmaceuticals 2025, 18(3), 414; https://doi.org/10.3390/ph18030414 - 14 Mar 2025
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Abstract
Background/Objectives: Herein, we demonstrate the development and characterization of ceftriaxone (CTX)-loaded liposomal nanoparticles (NPs) intended to be applicable to the management of lower respiratory tract infections (LRTIs) associated with resistant bacteria. Methods: The CTX-loaded liposomal NPs were fabricated by a thin film hydration [...] Read more.
Background/Objectives: Herein, we demonstrate the development and characterization of ceftriaxone (CTX)-loaded liposomal nanoparticles (NPs) intended to be applicable to the management of lower respiratory tract infections (LRTIs) associated with resistant bacteria. Methods: The CTX-loaded liposomal NPs were fabricated by a thin film hydration approach. Results: The particle size of the NPs, determined by a Zetasizer, was within the range of 90–536 nm. Microscopic examination by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) revealed that particles are spherical in shape and have retained their original morphology even after freeze-drying. Attenuated total reflection-Fourier transform infrared (ATR-FTIR), differential scanning calorimetry (DSC), thermogravimetric (TG), and powder X-ray diffraction (PXRD) spectra exhibited that CTX is incorporated into the liposomes with no possible interaction between drug and excipients. The formation of the CTX-loaded liposomal NPs was dependent on the concentrations of phospholipids, cholesterol and mannitol; however, no considerable differences were observed in entrapment efficiency and loading capacity of CTX formulations (F6–F10). Using a twin-stage impinger (TSI), the in vitro aerosolization of the formulations were carried out at a flow rate of 60 ± 5 L/min and CTX was determined by a validated HPLC method and the prepared liposomal formulations produced promising fine particle fraction (FPF) between 47 and 62%. The prepared formulation (F6) showed prolonged CTX release of 94.0% ± 5.7 and 95.9% ± 3.9 at 24 h and 48 h, respectively. The drug release followed the Hixon–Crowell model, with CTX being transported through Fickian diffusion. Conclusions: These results highlight the prepared CTX-loaded inhaled liposomal formulation would be suitable for pulmonary delivery and extend the successful antibiotic delivery strategies for the effective management of LRTIs. Full article
(This article belongs to the Special Issue Recent Advances in Inhalation Therapy)
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53 pages, 5164 KiB  
Review
From Traditional Efficacy to Drug Design: A Review of Astragali Radix
by Xiaojie Jin, Huijuan Zhang, Xiaorong Xie, Min Zhang, Ruifeng Wang, Hao Liu, Xinyu Wang, Jiao Wang, Dangui Li, Yaling Li, Weiwei Xue, Jintian Li, Jianxin He, Yongqi Liu and Juan Yao
Pharmaceuticals 2025, 18(3), 413; https://doi.org/10.3390/ph18030413 - 14 Mar 2025
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Abstract
Astragali Radix (AR), a traditional Chinese herbal medicine, is derived from the dried roots of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao (A. membranaceus var. mongholicus, AMM) or Astragalus membranaceus (Fisch.) Bge (A. membranaceus, AM). According to traditional Chinese medicine [...] Read more.
Astragali Radix (AR), a traditional Chinese herbal medicine, is derived from the dried roots of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao (A. membranaceus var. mongholicus, AMM) or Astragalus membranaceus (Fisch.) Bge (A. membranaceus, AM). According to traditional Chinese medicine (TCM) theory, AR is believed to tonify qi, elevate yang, consolidate the body’s surface to reduce sweating, promote diuresis and reduce swelling, generate body fluids, and nourish the blood. It has been widely used to treat general weakness and chronic illnesses and to improve overall vitality. Extensive research has identified various medicinal properties of AR, including anti-tumor, antioxidant, cardiovascular-protective, immunomodulatory, anti-inflammatory, anti-diabetic, and neuroprotective effects. With advancements in technology, methods such as computer-aided drug design (CADD) and artificial intelligence (AI) are increasingly being applied to the development of TCM. This review summarizes the progress of research on AR over the past decades, providing a comprehensive overview of its traditional efficacy, botanical characteristics, drug design and distribution, chemical constituents, and phytochemistry. This review aims to enhance researchers’ understanding of AR and its pharmaceutical potential, thereby facilitating further development and utilization. Full article
(This article belongs to the Section Natural Products)
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24 pages, 854 KiB  
Article
Evaluating the Use of Inhaled Budesonide and Ipratropium Bromide Combination in Patients at High Risk of Acute Respiratory Distress Syndrome Development: A Randomized Controlled Trial
by Hebatallah Ahmed Mohamed Moustafa, Faten H. Elbery, Ahmad Z. Al Meslamani, Sherouk M. Okda, Bshra A. Alsfouk and Amira B. Kassem
Pharmaceuticals 2025, 18(3), 412; https://doi.org/10.3390/ph18030412 - 14 Mar 2025
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Abstract
Objectives: There is a scarcity of pharmacological treatments that efficiently address lung injury in individuals experiencing acute respiratory distress syndrome (ARDS). Early inhaled corticosteroids and ipratropium may reduce pulmonary inflammation and injury of the lungs, minimizing the risk of ARDS. Method: This is [...] Read more.
Objectives: There is a scarcity of pharmacological treatments that efficiently address lung injury in individuals experiencing acute respiratory distress syndrome (ARDS). Early inhaled corticosteroids and ipratropium may reduce pulmonary inflammation and injury of the lungs, minimizing the risk of ARDS. Method: This is a double-blinded randomized control trial conducted on patients at risk of ARDS. Patients were randomly allocated into two groups; the intervention group (63 patients) were administered aerosolized budesonide and ipratropium bromide, and the control group (56) were administered a placebo every eight hours for five days. Alteration in oxygen saturation divided by inspired oxygen (Fio2) (S/F) after five days was the primary outcome. Secondary outcomes included ARDS occurrence, mechanical ventilation (MV) requirement, hospital stay duration, and mortality rates. Results: Of the 604 screened, only 119 patients were included. The intervention group (63 patients) S/F ratio recovered versus the fall of the control group. Both groups had similar organ dysfunction and 28-day mortality. The intervention group had significantly (p < 0.001) fewer cases developing ARDS (9.5%) and MV (9.5%) than the control group (46.4% and 35.7%, respectively). Conclusions: The administration of inhaled budesonide and ipratropium bromide improved oxygenation, as assessed by the S/F ratio, and significantly reduced the rate of ARDS development and the requirement of MV versus the control group. Larger multi-center trials including diverse patient populations are needed to validate these results. Full article
(This article belongs to the Section Pharmacology)
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18 pages, 1586 KiB  
Article
The Impact of Comorbidities on the Discontinuation of Antifibrotic Therapy in Patients with Idiopathic Pulmonary Fibrosis
by Stefano Kette, Nicolò Reccardini, Francesco Salton, Paola Confalonieri, Alessia Andrisano, Maria Chianese, Anna De Nes, Marta Maggisano, Alessandra Galantino, Salvatore Nicolosi, Marco Mari, Andrea Salotti, Darina Angoni, Maria Chernovsky, Michael Hughes, Marco Confalonieri, Lucrezia Mondini and Barbara Ruaro
Pharmaceuticals 2025, 18(3), 411; https://doi.org/10.3390/ph18030411 - 14 Mar 2025
Viewed by 440
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown aetiology. Evidence on the progression of idiopathic pulmonary fibrosis (IPF) following the introduction of antifibrotic therapies still indicates a generally poor prognosis. IPF is associated with both respiratory and non-respiratory [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown aetiology. Evidence on the progression of idiopathic pulmonary fibrosis (IPF) following the introduction of antifibrotic therapies still indicates a generally poor prognosis. IPF is associated with both respiratory and non-respiratory comorbidities, which can worsen symptoms and impact overall survival. Background/Objectives: The study aimed to investigate the effect of these comorbidities on the early and permanent discontinuation of pirfenidone or nintedanib in IPF patients. Methods: In this single-centre retrospective study, 101 patients diagnosed with IPF according to ATS/ERS/JRS/ALAT guidelines were treated with AFT. Clinical data were collected at 12 months prior to and up to 24 months following treatment initiation, including age, gender, smoking history, and the presence of respiratory and non-respiratory comorbidities. Results: The data showed that 21 patients (20.8%) discontinued treatment within the first 12 months. Additionally, pre-treatment comorbidities were not statistically correlated with the suspension of antifibrotic treatment. Among the overall cohort, 77 patients (76.2%) had at least one comorbidity and 27 (26.7%) had three or more comorbidities. Notably, 24 (23.8%) had respiratory comorbidities, while 75 (74.3%) had non-respiratory comorbidities. Conclusions: This real-life study emphasises the complexities involved in managing IPF, particularly regarding adherence to treatment when significant comorbidities are present. The evidence suggests that in patients with IPF, pre-treatment respiratory or non-respiratory conditions do not affect AFT discontinuation. Full article
(This article belongs to the Section Pharmacology)
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