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Design, Synthesis and Structure-Activity Relationship of Biologically Active Inhibitors

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 September 2024) | Viewed by 18158

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Dr. Santo Previti

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Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, Italy
Interests: peptide-based inhibitors; peptidomimetics; bioactive inhibitors; cysteine proteases; neurotensin; radiopharmaceutical; pain management
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Dr. Roberta Ettari

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Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, Italy
Interests: peptide-based inhibitors; peptidomimetics; bioactive inhibitors; cysteine proteases; proteasome; anticancer; inhibitors from nature; drug-combination studies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent decades, various approaches, such as structure-based design and high-throughput screening assays, have led to the identification of biologically active inhibitors with broad therapeutic actions.

Bioactive inhibitors are agents with the ability to:

Downregulate or block the expression of proteins, with consequent growth disruption;
Prevent protein–protein interactions, which leads to controlling compromised and abnormal pathways;
Block the catalytic activity of enzymes, resulting in a lower enzymatic activity and therapeutic benefits.

The impressive efforts made to identify molecules which disrupt pivotal processes in cancer, organ dysfunction, metabolic disorders, and infectious diseases led to a huge number of bioactive inhibitors marketed globally.

Despite the achievements, the development of more potent, safe, selective, and drug-like bioactive inhibitors is still a major challenge. In fact, several issues, such as drug resistance and toxicity, strongly limit the effectiveness of therapies.

This Special Issue aims to collect research articles reporting the development of biologically active inhibitors with anticancer and antimicrobial activity, as well as inhibitors useful to treat metabolic disorders and organ dysfunction. Review articles describing structure–activity relationships with detailed data for the drug discovery process are also welcome.

Dr. Santo Previti
Dr. Roberta Ettari
Guest Editors

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Keywords

biologically active inhibitors
anticancer
antimicrobial
metabolic disorders
enzyme inhibition
protein–protein interaction
protein expression

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Published Papers (9 papers)

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Research

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32 pages, 120311 KiB

Open AccessArticle

Serine/Threonine Protein Kinases as Attractive Targets for Anti-Cancer Drugs—An Innovative Approach to Ligand Tuning Using Combined Quantum Chemical Calculations, Molecular Docking, Molecular Dynamic Simulations, and Network-like Similarity Graphs

by Magdalena Latosińska and Jolanta Natalia Latosińska

Molecules 2024, 29(13), 3199; https://doi.org/10.3390/molecules29133199 - 5 Jul 2024

Cited by 1 | Viewed by 1753

Abstract

Serine/threonine protein kinases (CK2, PIM-1, RIO1) are constitutively active, highly conserved, pleiotropic, and multifunctional kinases, which control several signaling pathways and regulate many cellular functions, such as cell activity, survival, proliferation, and apoptosis. Over the past decades, they have gained increasing attention as potential therapeutic targets, ranging from various cancers and neurological, inflammation, and autoimmune disorders to viral diseases, including COVID-19. Despite the accumulation of a vast amount of experimental data, there is still no “recipe” that would facilitate the search for new effective kinase inhibitors. The aim of our study was to develop an effective screening method that would be useful for this purpose. A combination of Density Functional Theory calculations and molecular docking, supplemented with newly developed quantitative methods for the comparison of the binding modes, provided deep insight into the set of desirable properties responsible for their inhibition. The mathematical metrics helped assess the distance between the binding modes, while heatmaps revealed the locations in the ligand that should be modified according to binding site requirements. The Structure-Binding Affinity Index and Structural-Binding Affinity Landscape proposed in this paper helped to measure the extent to which binding affinity is gained or lost in response to a relatively small change in the ligand’s structure. The combination of the physico-chemical profile with the aforementioned factors enabled the identification of both “dead” and “promising” search directions. Tests carried out on experimental data have validated and demonstrated the high efficiency of the proposed innovative approach. Our method for quantifying differences between the ligands and their binding capabilities holds promise for guiding future research on new anti-cancer agents. Full article

(This article belongs to the Special Issue Design, Synthesis and Structure-Activity Relationship of Biologically Active Inhibitors)

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21 pages, 1558 KiB

Open AccessArticle

Design, Synthesis, Antitumor, and Antiplasmodial Evaluation of New 7-Chloroquinoline–Benzimidazole Hybrids

by Luka Krstulović, Vesna Rastija, Lais Pessanha de Carvalho, Jana Held, Zrinka Rajić, Zorislava Živković, Miroslav Bajić and Ljubica Glavaš-Obrovac

Molecules 2024, 29(13), 2997; https://doi.org/10.3390/molecules29132997 - 24 Jun 2024

Viewed by 882

Abstract

Newly synthesized 7-chloro-4-aminoquinoline–benzimidazole hybrids were characterized by NMR and elemental analysis. Compounds were tested for their effects on the growth of the non-tumor cell line MRC-5 (human fetal lung fibroblasts) and carcinoma (HeLa and CaCo-2), leukemia, and lymphoma (Hut78, THP-1, and HL-60) cell lines. The obtained results, expressed as the concentration at which 50% inhibition of cell growth is achieved (IC₅₀ value), show that the tested compounds affect cell growth differently depending on the cell line and the applied dose (IC₅₀ ranged from 0.2 to >100 µM). Also, the antiplasmodial activity of these hybrids was evaluated against two P. falciparum strains (Pf3D7 and PfDd2). The tested compounds showed potent antiplasmodial activity, against both strains, at nanomolar concentrations. Quantitative structure–activity relationship (QSAR) analysis resulted in predictive models for antiplasmodial activity against the 3D7 strain (R² = 0.886; R_ext² = 0.937; F = 41.589) and Dd2 strain (R² = 0.859; R_ext² = 0.878; F = 32.525) of P. falciparum. QSAR models identified the structural features of these favorable effects on antiplasmodial activities. Full article

(This article belongs to the Special Issue Design, Synthesis and Structure-Activity Relationship of Biologically Active Inhibitors)

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15 pages, 2640 KiB

Open AccessArticle

SAR, Molecular Docking and Molecular Dynamic Simulation of Natural Inhibitors against SARS-CoV-2 Mpro Spike Protein

by Aqsa Salamat, Naveen Kosar, Ayesha Mohyuddin, Muhammad Imran, Muhammad Nauman Zahid and Tariq Mahmood

Molecules 2024, 29(5), 1144; https://doi.org/10.3390/molecules29051144 - 4 Mar 2024

Viewed by 1956

Abstract

The SARS-CoV-2 virus and its mutations have affected human health globally and created significant danger for the health of people all around the world. To cure this virus, the human Angiotensin Converting Enzyme-2 (ACE2) receptor, the SARS-CoV-2 main protease (Mpro), and spike proteins were found to be likely candidates for the synthesis of novel therapeutic drug. In the past, proteins were capable of engaging in interaction with a wide variety of ligands, including both manmade and plant-derived small molecules. Pyrus communis L., Ginko bibola, Carica papaya, Syrian rue, and Pimenta dioica were some of the plant species that were studied for their tendency to interact with SARS-CoV-2 main protease (Mpro) in this research project (6LU7). This scenario investigates the geometry, electronic, and thermodynamic properties computationally. Assessing the intermolecular forces of phytochemicals with the targets of the SARS-CoV-2 Mpro spike protein (SP) resulted in the recognition of a compound, kaempferol, as the most potent binding ligand, −7.7 kcal mol⁻¹. Kaempferol interacted with ASP-187, CYS-145, SER-144, LEU 141, MET-165, and GLU-166 residues. Through additional molecular dynamic simulations, the stability of ligand–protein interactions was assessed for 100 ns. GLU-166 remained intact with 33% contact strength with phenolic OH group. We noted a change in torsional conformation, and the molecular dynamics simulation showed a potential variation in the range from 3.36 to 7.44 against a 45–50-degree angle rotation. SAR, pharmacokinetics, and drug-likeness characteristic investigations showed that kaempferol may be the suitable candidate to serve as a model for designing and developing new anti-COVID-19 medicines. Full article

(This article belongs to the Special Issue Design, Synthesis and Structure-Activity Relationship of Biologically Active Inhibitors)

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46 pages, 18097 KiB

Open AccessArticle

Favipiravir Analogues as Inhibitors of SARS-CoV-2 RNA-Dependent RNA Polymerase, Combined Quantum Chemical Modeling, Quantitative Structure–Property Relationship, and Molecular Docking Study

by Magdalena Latosińska and Jolanta Natalia Latosińska

Molecules 2024, 29(2), 441; https://doi.org/10.3390/molecules29020441 - 16 Jan 2024

Cited by 4 | Viewed by 1800

Abstract

Our study was motivated by the urgent need to develop or improve antivirals for effective therapy targeting RNA viruses. We hypothesized that analogues of favipiravir (FVP), an inhibitor of RNA-dependent RNA polymerase (RdRp), could provide more effective nucleic acid recognition and binding processes while reducing side effects such as cardiotoxicity, hepatotoxicity, teratogenicity, and embryotoxicity. We proposed a set of FVP analogues together with their forms of triphosphate as new SARS-CoV-2 RdRp inhibitors. The main aim of our study was to investigate changes in the mechanism and binding capacity resulting from these modifications. Using three different approaches, QTAIM, QSPR, and MD, the differences in the reactivity, toxicity, binding efficiency, and ability to be incorporated by RdRp were assessed. Two new quantum chemical reactivity descriptors, the relative electro-donating and electro-accepting power, were defined and successfully applied. Moreover, a new quantitative method for comparing binding modes was developed based on mathematical metrics and an atypical radar plot. These methods provide deep insight into the set of desirable properties responsible for inhibiting RdRp, allowing ligands to be conveniently screened. The proposed modification of the FVP structure seems to improve its binding ability and enhance the productive mode of binding. In particular, two of the FVP analogues (the trifluoro- and cyano-) bind very strongly to the RNA template, RNA primer, cofactors, and RdRp, and thus may constitute a very good alternative to FVP. Full article

(This article belongs to the Special Issue Design, Synthesis and Structure-Activity Relationship of Biologically Active Inhibitors)

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23 pages, 13554 KiB

Open AccessArticle

Structure–Activity Studies on Bis-Sulfonamide SHIP1 Activators

by Shea T. Meyer, Sandra Fernandes, Robert E. Anderson, Angela Pacherille, Bonnie Toms, William G. Kerr and John D. Chisholm

Molecules 2023, 28(24), 8048; https://doi.org/10.3390/molecules28248048 - 12 Dec 2023

Viewed by 1156

Abstract

The SH2-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) enzyme opposes the activity of PI3K and therefore is of interest in the treatment of inflammatory disorders. Recent results also indicate that SHIP1 promotes phagolysosomal degradation of lipids by microglia, suggesting that the enzyme may be a target for the treatment of Alzheimer’s disease. Therefore, small molecules that increase SHIP1 activity may have benefits in these areas. Recently we discovered a bis-sulfonamide that increases the enzymatic activity of SHIP1. A series of similar SHIP1 activators have been synthesized and evaluated to determine structure–activity relationships and improve in vivo stability. Some new analogs have now been found with improved potency. In addition, both the thiophene and the thiomorpholine in the parent structure can be replaced by groups without a low valent sulfur atom, which provides a way to access activators that are less prone to oxidative degradation. Full article

(This article belongs to the Special Issue Design, Synthesis and Structure-Activity Relationship of Biologically Active Inhibitors)

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15 pages, 3355 KiB

Open AccessArticle

IGF2 Peptide-Based LYTACs for Targeted Degradation of Extracellular and Transmembrane Proteins

by Michał Mikitiuk, Jan Barczyński, Przemysław Bielski, Marcelino Arciniega, Urszula Tyrcha, Aleksandra Hec, Andrea D. Lipińska, Michał Rychłowski, Tad A. Holak and Tomasz Sitar

Molecules 2023, 28(22), 7519; https://doi.org/10.3390/molecules28227519 - 10 Nov 2023

Cited by 2 | Viewed by 3267

Abstract

Lysosome-targeting chimeras (LYTACs) have recently been developed to facilitate the lysosomal degradation of specific extracellular and transmembrane molecular targets. However, the LYTAC particles described to date are based on glycopeptide conjugates, which are difficult to prepare and produce on a large scale. Here, we report on the development of pure protein LYTACs based on the non-glycosylated IGF2 peptides, which can be readily produced in virtually any facility capable of monoclonal antibody production. These chimeras utilize the IGF2R/CI-M6PR pathway for lysosomal shuttling and, in our illustrative example, target programmed death ligand 1 (PD-L1), eliciting physiological effects analogous to immune checkpoint blockade. Results from in vitro assays significantly exceed the effects of anti-PD-L1 antibodies alone. Full article

(This article belongs to the Special Issue Design, Synthesis and Structure-Activity Relationship of Biologically Active Inhibitors)

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13 pages, 1335 KiB

Open AccessArticle

Evaluation of 4-Aminoquinoline Hydrazone Analogues as Potential Leads for Drug-Resistant Malaria

by Rachael N. Magwaza, Muna Abubaker, Buthaina Hussain, Michael Haley, Kevin Couper, Sally Freeman and Niroshini J. Nirmalan

Molecules 2023, 28(18), 6471; https://doi.org/10.3390/molecules28186471 - 6 Sep 2023

Cited by 3 | Viewed by 1753

Abstract

The emergence of resistance to first-line antimalarial drugs calls for the development of new therapies for drug-resistant malaria. The efficacy of quinoline-based antimalarial drugs has prompted the development of novel quinolines. A panel of 4-aminoquinoline hydrazone analogues were tested on the multidrug-resistant K1 strain of Plasmodium falciparum: IC₅₀ values after a 48 h cycle ranged from 0.60 to 49 µM, while the 72 h cycle ranged from 0.026 to 0.219 μM. Time-course assays were carried out to define the activity of the lead compounds, which inhibited over 50% growth in 24 h and 90% growth in 72 h. Cytotoxicity assays with HepG2 cells showed IC₅₀ values of 0.87–11.1 μM, whereas in MDBK cells, IC₅₀ values ranged from 1.66 to 11.7 μM. High selectivity indices were observed for the lead compounds screened at 72 h on P. falciparum. Analyses of stage specificity revealed that the ring stages of the parasite life cycle were most affected. Based on antimalarial efficacy and in vitro safety profiles, lead compound 4-(2-benzylidenehydrazinyl)-6-methoxy-2-methylquinoline 2 was progressed to drug combination studies for the detection of synergism, with a combinatory index of 0.599 at IC₉₀ for the combination with artemether, indicating a synergistic antimalarial activity. Compound 2 was screened on different strains of P. falciparum (3D7, Dd2), which maintained similar activity to K1, suggesting no cross-resistance between multidrug resistance and sensitive parasite strains. In vivo analysis with 2 showed the suppression of parasitaemia with P. yoelii NL (non-lethal)-treated mice (20 mg/kg and 5 mg/kg). Full article

(This article belongs to the Special Issue Design, Synthesis and Structure-Activity Relationship of Biologically Active Inhibitors)

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15 pages, 3545 KiB

Open AccessArticle

The Mechanism of Anti-Tumor Activity of 6-Morpholino- and 6-Amino-9-Sulfonylpurine Derivatives on Human Leukemia Cells

by Marijana Leventić, Teuta Opačak-Bernardi, Vesna Rastija, Josipa Matić, Dijana Pavlović Saftić, Željka Ban, Biserka Žinić and Ljubica Glavaš-Obrovac

Molecules 2023, 28(16), 6136; https://doi.org/10.3390/molecules28166136 - 19 Aug 2023

Cited by 1 | Viewed by 1286

Abstract

The aim of this study was to explore the mechanism of antitumor effect of (E)-6-morpholino-9-(styrylsulfonyl)-9H-purine (6-Morpholino-SPD) and (E)-6-amino-9-(styrylsulfonyl)-9H-purine (6-Amino-SPD). The effects on apoptosis induction, mitochondrial potential, and accumulation of ROS in treated K562 cells were determined by flow cytometry. The RT-PCR method was used to measure the expression of Akt, CA IX, caspase 3, and cytochrome c genes, as well as selected miRNAs. Western blot analysis was used to determine the expression of Akt, cytochrome c, and caspase 3. The results demonstrate the potential of the tested derivatives as effective antitumor agents with apoptotic-inducing properties. In leukemic cells treated with 6-Amino-SPD, increased expression of caspase 3 and cytochrome c genes was observed, indicating involvement of the intrinsic mitochondrial pathway in the induction of apoptosis. Conversely, leukemic cells treated with 6-Morpholino-SPD showed reduced expression of these genes. The observed downregulation of miR-21 by 6-Morpholino-SPD may contribute to the induction of apoptosis and disruption of mitochondrial function. In addition, both derivatives exhibited increased expression of Akt and CA IX genes, suggesting activation of the Akt/HIF pathway. However, the exact mechanism and its relations to the observed overexpression of miR-210 need further investigation. The acceptable absorption and distribution properties predicted by ADMET analysis suggest favorable pharmacokinetic properties for these derivatives. Full article

(This article belongs to the Special Issue Design, Synthesis and Structure-Activity Relationship of Biologically Active Inhibitors)

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Review

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50 pages, 13356 KiB

Open AccessReview

Indole-Based Compounds as Potential Drug Candidates for SARS-CoV-2

by Adel S. Girgis, Siva S. Panda, Benson M. Kariuki, Mohamed S. Bekheit, Reham F. Barghash and Dalia R. Aboshouk

Molecules 2023, 28(18), 6603; https://doi.org/10.3390/molecules28186603 - 13 Sep 2023

Cited by 7 | Viewed by 2760

Abstract

The COVID-19 pandemic has posed a significant threat to society in recent times, endangering human health, life, and economic well-being. The disease quickly spreads due to the highly infectious SARS-CoV-2 virus, which has undergone numerous mutations. Despite intense research efforts by the scientific community since its emergence in 2019, no effective therapeutics have been discovered yet. While some repurposed drugs have been used to control the global outbreak and save lives, none have proven universally effective, particularly for severely infected patients. Although the spread of the disease is generally under control, anti-SARS-CoV-2 agents are still needed to combat current and future infections. This study reviews some of the most promising repurposed drugs containing indolyl heterocycle, which is an essential scaffold of many alkaloids with diverse bio-properties in various biological fields. The study also discusses natural and synthetic indole-containing compounds with anti-SARS-CoV-2 properties and computer-aided drug design (in silico studies) for optimizing anti-SARS-CoV-2 hits/leads. Full article

(This article belongs to the Special Issue Design, Synthesis and Structure-Activity Relationship of Biologically Active Inhibitors)

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