Search Results (408)

Background: Peripheral neuropathy is a common and clinically heterogeneous neurological condition caused by metabolic, inflammatory, toxic, or traumatic factors and is associated with sensory deficits, neuropathic pain, motor impairment, and reduced functional capacity. Management remains challenging and often requires multimodal therapeutic approaches, as pharmacological monotherapy frequently provides incomplete symptom control. Objective: This narrative review explores the conceptual rationale for combining galantamine with iontophoresis and Black Sea brine-based therapy as a potential multimodal strategy for peripheral neuropathy management. Main Findings: Galantamine, a reversible acetylcholinesterase inhibitor and positive allosteric modulator of nicotinic acetylcholine receptors, has demonstrated neuroprotective, neuromodulatory, and anti-inflammatory properties in experimental settings. Iontophoresis may provide a non-invasive method for targeted local drug delivery while reducing systemic exposure. Black Sea brine, widely used in Bulgarian balneological and rehabilitation practice, has been associated with improved circulation, pain reduction, and neuromuscular support. The reviewed evidence suggests biologically plausible complementary mechanisms; however, no direct clinical studies evaluating the combined intervention were identified. Limitations: Current evidence is indirect and derived from separate investigations of galantamine, iontophoresis, and brine-based therapy, as well as heterogeneous historical and regional sources. Therefore, the proposed combination should be considered hypothesis-generating rather than evidence-established. Conclusions: The combination of galantamine, iontophoresis, and Black Sea brine represents a potentially interesting multimodal concept for peripheral neuropathy rehabilitation. Well-designed preclinical and clinical studies are required to determine safety, feasibility, optimal treatment parameters, and therapeutic efficacy. Full article

Coronavirus disease 2019 continues to pose global health challenges, with the pandemic significantly burdening several economies, healthcare systems, and the social lives of individuals. Furthermore, new cases continue to be reported, underscoring the need for therapeutic strategies targeting conserved regions and host–virus interactions. Building on earlier virtual screening for small molecules, all-atom molecular dynamics simulations and binding-free-energy calculations were performed to elucidate how the two previously identified small molecules (NSC36398 and NSC281245) may affect the dynamic behaviour of the interaction between heat shock 70 kDa protein 8 (HSPA8) and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein. Post-MD analyses refined prior docking predictions, where NSC281245 was found to bind tightly to the complex with limited perturbations at the HSPA8-spike protein interaction surface, whereas NSC36398 appeared to induce allosteric-like domain-level destabilisation effects while maintaining stable polar contacts with the protein. Our findings demonstrate the potential of NSC36398 as a promising modulator for disrupting the HSPA8-spike protein complex, which may serve as a structural lead for designing next-generation inhibitors of host–virus interactions. Full article

The antimicrobial resistance of Acinetobacter baumannii necessitates the development of novel therapeutic strategies targeting essential enzymes such as Undecaprenyl Pyrophosphate Phosphatase (UppP). This study explored spider venom peptides in silico as potential allosteric inhibitors of A. baumannii UppP. A systematic literature review was conducted to select eight α-helical peptides with reported anti-A. baumannii activity, followed by their computational physicochemical characterization. Three-dimensional models of A. baumannii UppP and the candidate peptides were generated, and a putative allosteric binding site was validated through molecular docking of a known inhibitor of the BacA homolog. The eight peptides were subsequently docked to this validated site using HADDOCK. Results revealed variable binding affinities; peptides LC-AMP-I1, Lycosin-II, and GK37 exhibited the most favorable HADDOCK scores and extensive interaction networks, consistent with their reported high antimicrobial potency. Other candidates, notably Lt-MAP2, showed low binding affinity but high predicted synergistic potential. These findings identify promising spider venom peptide candidates, suggesting dual (membrane disruption/UppP inhibition) or synergistic mechanisms of action, and validate UppP as a viable pharmacological target for peptide-based inhibitors. Full article

Galectin-3 (Gal3) is one of the most pro-inflammatory proteins and a biomarker of inflammatory diseases and cancer. Previous studies showed that Gal3 binds to αv and β1 integrins, but it is unclear how Gal3 binds to integrins. Here, we show that Gal3 bound to soluble αvβ3 and αIIbβ3 integrins in 1 mM Mn²⁺ in cell-free conditions in a glycan-independent manner. Docking simulation predicts that Gal3 binds to the classical RGD-binding site (site 1) of αvβ3, but the predicted Gal3-binding site does not include galactose-binding site. RGDfV or eptifibatide inhibited Gal3 binding to αvβ3 and αIIbβ3, respectively, but lactose, a pan-galectin inhibitor, did not inhibit Gal3 binding to integrins. Point mutations of the predicted site 1 binding interface of Gal3 effectively inhibited Gal3 binding to site 1. Site 2 is involved in pro-inflammatory signaling (e.g., TNF and IL-6 secretion), and we previously showed that pro-inflammatory cytokines (e.g., CCL5 and TNF) bind to site 2 and allosteric integrin activation. Docking simulation predicted that Gal3 binds to site 2 of αvβ3 and α5β1. We found that Gal3 induced allosteric activation of soluble integrins αvβ3, αIIbβ3, and α5β1 in 1 mM Ca²⁺ in cell-free conditions. Point mutations in the predicted site 2 binding interface inhibited Gal3-induced integrin activation, suggesting that Gal3 binding to site 2 is required for Gal3-induced integrin activation. Known anti-inflammatory agents, Ivermectin, NRG1, and FGF1, inhibited integrin activation induced by Gal3 in αvβ3 and αIIbβ3. These findings suggest that Gal3 binding to site 2 may be a potential mechanism of pro-inflammatory and pro-thrombotic action of Gal3. Full article

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) remains a high-risk entity despite advances in tyrosine kinase inhibitors (TKIs), immunotherapy, and cellular therapies. Relapse driven by clonal evolution, central nervous system (CNS) sanctuary disease, and TKI resistance, particularly T315I mutations, continues to limit durable disease control. Asciminib, a first-in-class allosteric BCR::ABL1 (STAMP) inhibitor, has demonstrated efficacy and favorable tolerability in chronic myeloid leukemia, but its optimal role in Ph+ ALL remains to be defined. We report a three-patient case series of Ph+ acute leukemia treated with asciminib across diverse high-risk clinical settings, including multiply relapsed disease, CNS involvement, T315I-mutated leukemia, post-CAR-T-cell relapses, and transplant bridging. Clinical outcomes are contextualized through a comprehensive review of emerging clinical trial data, real-world cohorts, and mechanistic studies evaluating asciminib in Ph+ ALL. Across all cases, asciminib was incorporated as part of combination or consolidation strategies rather than as monotherapy in active disease. Asciminib contributed to molecular disease control, CNS leukemia clearance, and successful bridging to allogeneic transplantation or cellular therapy, with acceptable tolerability and no major vascular toxicity. Integration of published evidence demonstrates that asciminib exhibits consistent biological activity in Ph+ ALL, with improved durability when used in rational combinations, particularly with immunotherapy or ATP-competitive TKIs. Preclinical data further support asciminib’s compatibility with antibody-based and cellular therapies through preservation of immune effector function. Asciminib represents a versatile but context-dependent therapeutic option in Ph+ ALL. Its greatest clinical value appears to lie in rational combination regimens, maintenance strategies, and bridging to definitive therapies rather than single-agent salvage. Emerging structural biomarkers and ongoing clinical trials are expected to further refine patient selection, sequencing, and optimal integration of asciminib, particularly in CNS-involved disease and post-CAR-T cell relapse. Full article

The polyamine metabolic pathway, an evolutionarily conserved nexus integrating nutrient sensing, translation control, and cellular proliferation, is fundamentally rewired in cancer. Melanoma, a malignancy of melanocytes notorious for its metastatic propensity and therapy resistance, exhibits a profound dependency on this pathway, extending beyond mere polyamine abundance to the specialized function of their derivative, hypusine. This review synthesizes cutting-edge insights into the deoxyhypusine synthase (DHPS)/eukaryotic initiation factor 5A (eIF5A) hypusination circuit as a critical amplifier of oncogenic signaling in melanoma. We dissect its role as a translational rheostat for pro-tumorigenic proteomes, a driver of phenotypic plasticity underpinning invasion and vasculogenic mimicry, and a modulator of the immunosuppressive tumor microenvironment. Moving beyond the classical inhibitor GC7, we explore the emergence of novel allosteric DHPS inhibitors with compelling preclinical efficacy. Finally, we propose a paradigm shift: targeting the DHPS/eIF5A axis represents a strategy to disrupt the “non-oncogene addiction” of melanoma—its reliance on hyperactive translation and adaptive survival mechanisms—offering a promising avenue alongside targeted therapies and immunotherapies. Full article

Neuroinflammation is determinant in the progression of neurodegenerative diseases. One of the main mechanisms underlying this process involves the persistent activation of glial cells. Persistent activation of glial cells induces proinflammatory transcription factors and the release of cytokines, chemokines, and reactive oxygen species that exacerbate cellular dysfunction. This neurotoxic environment promotes neuronal death, while the products of cellular damage feed back into glial activation, establishing a self-sustaining pathogenic cycle that drives neurodegeneration. Alkaloids present in Amaryllidaceae plants support the use of this resource in folk medicine, displaying potent effects as acetylcholinesterase inhibitors and allosteric modulators of nicotinic receptors (nAChR). In this study, a murine microglial cell (IMG) model of LPS-induced inflammation was used to evaluate the involvement of α7 and α4β2 nAChRs in glioprotection and neuroprotection of SH-SY5Y cells against 6-hydroxydopamine (OHDA). GC-MS analysis revealed differences in the alkaloid profile between in vitro cultures with fructose and wild-type Rhodophiala pratensis. Homolycorine-type, norbelladine-type and crinine-type alkaloids produced in vitro reduced LPS-induced inflammation (5 µg/mL), possibly via α7 and α4β2 nAChRs, and showed a protective effect against OHDA-induced oxidative stress (1–3 µg/mL) and inhibited AChE and BuChE (24–78 µg/mL). Full article

Background: Point mutations to the androgen receptor (AR) ligand-binding domain (LBD) are becoming increasingly recognized as a mechanism of therapeutic resistance in castration resistant prostate cancer (CRPC). The present review explores how point mutations induce molecular changes that contribute to the eventual treatment failure of androgen receptor pathway inhibitors (ARPIs) in CRPC. Methods: The PubMed database was searched for structural studies on the AR LBD. Eligible articles included molecular docking analysis and emphasized changes in ligand–receptor interactions after point mutation. Structural data were obtained from the Protein Data Bank (PDB) using the search parameters “Androgen receptor ligand binding domain”, “Homo sapiens”, and “X-ray diffraction”. PDB files of wild-type and point mutant AR LBDs were accumulated for analysis. Results: A functional shift from inhibiting to activating AR has been documented for multiple ARPIs. Crystallography data and in silico evaluation have deciphered how changes in steric hindrance of the AF-2 domain contribute to ARPI loss of function. To combat therapeutic resistance, discovery efforts have begun to consider combination approaches of orthosteric and allosteric inhibitors, as well as compounds that target other AR domains. Although lead compounds have been identified, none have progressed into the clinic. Conclusions: Questions remain regarding the best approach for rationally designing new AR targeting therapeutics. Understanding how structural changes to the AR LBD lead to the failure of clinical therapeutics is a necessary step that should precede drug discovery campaigns. Moreover, computational modeling is a powerful tool that should be leveraged to streamline therapeutic development. Full article

The berberine derivative 13-(2-methylbenzyl)-berberine (BED) has been shown to inhibit the MexXY-OprM efflux system of Pseudomonas aeruginosa (PA), a key contributor to aminoglycoside resistance, by interacting with the inner membrane protein MexY at an allosteric pocket (ALP). To enhance binding efficacy, this study aims to identify novel chemical scaffolds that target the MexY allosteric pocket through an integrated computational strategy. In this work, a ligand-based virtual screening (LBVS) approach was employed using a 2D/3D pharmacophore model derived from BED to perform in silico screening of an Enamine compound library, which encompasses a broad and diverse chemical space. A key objective was to compare the predictive performance of this pharmacophore-based workflow with a structure-based (SB) strategy incorporating molecular docking and molecular dynamics (MD) simulations. Notably, the top-ranked LBVS hits were consistently validated by docking and MD analyses, showing stable binding and interaction patterns comparable or superior to those of BED. This convergence between ligand-based (LB) and SB methods highlights the internal coherence of the workflow and supports the robustness of the pharmacophore hypothesis. The identified scaffolds generally displayed high hydrophobicity, consistent with the physicochemical nature of the binding site, but resulting in limited aqueous solubility and complicating their experimental evaluation. While these features confirm the importance of hydrophobic interactions in MexY recognition, with a particular focus on some few residues, such as Phe560, it also underscores the need for formulation strategies or rational scaffold modifications introducing moderate polarity without weakening key contacts. Overall, the integrated computational strategy not only yields promising lead chemical structures but also provides a solid basis for their future optimization, ultimately supporting the design of new efflux pump inhibitors (EPIs) capable of contributing to improved antibiotic susceptibility in multidrug-resistant PA strains. Full article

Peptidyl arginine deiminase 4 (PAD4) is a Ca²⁺-dependent enzyme that catalyzes histone citrullination and plays a central role in chromatin decondensation during neutrophil extracellular trap (NET) formation. Dysregulated PAD4-mediated NETosis contributes to the pathogenesis of diverse inflammatory and immune-related diseases, including autoimmune disorders, cancer, and thrombosis. Although several synthetic PAD4 inhibitors have been developed, their therapeutic application has been limited by issues related to selectivity, irreversible covalent reactivity, and suboptimal pharmacokinetic properties, prompting growing interest in natural products as alternative modulators of PAD4 activity and NETosis. This article presents a structural and mechanistic overview of natural products that target PAD4 and regulate NETosis. Based on enzyme kinetics, structural analyses, and functional validation, natural PAD4 modulators are classified into four categories: (i) active-site-directed inhibitors that bind within the U-shaped substrate tunnel, (ii) mixed and active-site-adjacent inhibitors that engage surface pockets flanking the catalytic site, (iii) allosteric and hybrid modulators that bind to regulatory regions distinct from the active site, and (iv) functionally validated PAD4 binders supported by biophysical and cellular evidence. Integration of structural, biochemical, and cellular data highlights that indirect or noncanonical modes of PAD4 regulation represent biologically coherent strategies for controlling pathological NETosis. Full article

Psoriasis is a chronic, immune-mediated inflammatory skin disease requiring effective long-term systemic treatment. Current options, including using conventional small molecules and biological therapies, are limited by adverse events, suboptimal efficacy, or poor adherence due to inconvenient administration. This highlights an unmet need for safe, convenient, and effective oral self-administered dosage form therapies aligned with patient preferences. This review evaluates the mechanism, safety, and efficacy of next-generation tyrosine kinase 2 (TYK2) inhibitors and compares them to currently available therapeutic options. The pathogenesis of psoriasis is driven by chronic systemic inflammation mediated by the interleukin-23 (IL-23)/Th17/interleukin-17 (IL-17) axis. Selective TYK2 inhibitors, such as deucravacitinib, envudeucitinib, and zasocitinib, act through a unique allosteric mechanism by binding to the regulatory pseudokinase domain (JH2) rather than the enzyme’s catalytic domain. This enables highly selective suppression of IL-23-mediated inflammation while mitigating systemic toxicity seen with nonselective Janus kinase (JAK) inhibitors. Clinical trials (POETYK PSO-1 and PSO-2) and long-term extension studies demonstrate that deucravacitinib provides superior efficacy compared to the first-generation oral small molecule apremilast, with high and sustained response rates. It maintains durable efficacy for up to four years in patients with moderate to severe plaque psoriasis and shows a stable long-term safety profile, with low incidence of major adverse cardiovascular events (MACEs), venous thromboembolism (VTE), serious infections, and malignancies. Selective TYK2 inhibition bridges the therapeutic gap, providing an optimal balance of efficacy and oral convenience. With the potential to improve patient adherence and quality of life, these agents represent a promising option to become a first-line oral systemic therapy for psoriasis. Full article

The rapid spread of antibiotic resistance through plasmid-mediated conjugation remains a primary global health concern. Despite its critical role in horizontal gene transfer, no approved drugs currently target this process, leaving a critical therapeutic gap. Integration Host Factor (IHF), a DNA-binding protein essential for plasmid replication and mobilization, emerges as a promising yet underexplored target for anti-conjugation strategies. This work aimed to develop a predictive computational model and identify small molecules that disrupt IHF function, thereby reducing plasmid transfer and limiting resistance gene dissemination. A curated dataset of 65 compounds with reported anti-plasmid activity was analyzed using a 3D-QSAR model based on algebraic descriptors computed with QuBiLS-MIDAS. The model was validated through leave-one-out cross-validation (Q² = 0.82), Tropsha’s criteria, and Y-scrambling. Representative compounds were selected via pharmacophore clustering and evaluated through molecular docking at both the DNA-binding site and a predicted allosteric pocket of IHF. The most promising complexes underwent 200 ns molecular dynamics simulations to assess stability and interaction patterns. The QSAR model demonstrated strong predictive performance (R² = 0.90). Docking simulations revealed more favorable binding energies at the allosteric site (up to −12.15 kcal/mol) compared to the DNA-binding site. Molecular dynamics confirmed the stability of these interactions, with allosteric complexes showing lower RMSD fluctuations and consistent binding energy profiles. Dynamic cross-correlation analysis revealed that allosteric ligand binding induces conformational changes in key catalytic residues, including Pro65, Pro61, and Leu66. These alterations may compromise DNA recognition and disrupt the initiation of replication. To our knowledge, this is the first computational study proposing allosteric inhibition of IHF as an anti-conjugation strategy. These findings provide a foundation for experimental validation and the development of novel agents to prevent horizontal gene transfer, offering a promising approach to restoring antibiotic efficacy against multidrug-resistant pathogens. Full article

Aldose Reductase (AR; AKR1B1) is an enzyme that plays a key role in the metabolism of glucose and other carbonyl compounds, and whose hyperactivity contributes to oxidative stress and vascular dysfunction. Despite decades of investigation into this enzyme, inhibitors have failed to translate into clinical application for Diabetic Retinopathy (DR). We argue that these failures might arise from non-selective inhibition, considering the dual roles of AR, which contribute not only to DR pathology but also support retinal health, as AR is an important detoxifying enzyme for aldehydes produced during oxidative stress. Here, we discuss missing structural information, despite more than one hundred crystal structures of AR in complex with inhibitors. Our review bridges this gap by discussing how recent advances in structural biology, e.g., fragment-based drug discovery and MicroED, provide novel ways to selectively modulate AR functions, offering advantages for the detection of weak, allosteric, or conformation-dependent binding events. Despite past challenges, we suggest that therapeutic targeting of AR to find new-generation inhibitors will become more effective once we have a clearer understanding of the requirements for selective inhibition of AR, blocking its pathological impact while preserving its physiological functions. By integrating fragment screening and structural biology, we outline a strategy to reinvigorate AR modulation as a viable retina-specific approach for managing DR, with potentially broader relevance toward multiple diabetic microvascular complications. Full article

This study investigated the α-glucosidase inhibitory potential of enzymatic/alkaline treatments from Palmaria palmata using different proteases and pairwise combinations thereof. Treatments prepared with Alcalase^®, Flavourzyme^®, and Formea^® Prime, alone or in combination, were evaluated for dose-dependent inhibitory activity. Alcalase^®-derived treatments exhibited the highest α-glucosidase inhibition, achieving an IC₅₀ of 2.48 mg·mL⁻¹, outperforming other treatments and combinations. Membrane fractionation of the Alcalase^®-derived treatment into >5 kDa, 3–5 kDa, 1–3 kDa, and <1 kDa fractions revealed a size-dependent trend, with the <1 kDa fraction showing the strongest inhibition (IC₅₀ of 1.94 mg·mL⁻¹). Three peptides, RADIPFRRA, DGIAEAWLG, and FWSQIFGVAF, from the <1 kDa fraction were identified as potential α-glucosidase inhibitors using the BIOPEP-UWM database and were further selected based on a Peptide Ranker score above 0.6 for in silico docking analyses. Docking revealed distinct binding modes: RADIPFRRA and DGIAEAWLG occupied the catalytic cleft, interacting with key residues (Asp518, Asp616, Trp481, Trp613) consistent with competitive inhibition, whereas FWSQIFGVAF bound to a peripheral site, suggesting potential allosteric modulation. Physicochemical analysis further highlighted differences in charge and isoelectric point correlating with their binding behavior. Together, these findings demonstrate that low-molecular-weight peptides derived from P. palmata proteins, particularly those generated by Alcalase^®, possess significant α-glucosidase inhibitory activity, and provide structural insights for the rational design of peptide-based modulators of carbohydrate metabolism. Full article

Emerging mosquito-borne flaviviruses, such as Dengue virus (DENV) and Zika virus (ZIKV), pose major global public health threats due to their geographic expansion, climate change, and the absence of effective antiviral therapies. Antiviral development against these pathogens has primarily focused on two complementary strategies. On the one hand, the blocking of viral replication by directly inhibiting essential viral enzymes, and on the other, enhancing the host’s innate immune defenses via targeted activation of intracellular antiviral pathways. Among the viral proteins required for replication, the NS2B–NS3 protease complex is one of the most conserved and druggable targets, prompting extensive efforts to design both covalent and non-covalent inhibitors. Covalent inhibitors, such as boronic acids, aldehydes, trifluoromethyl ketones, phenoxymethylphenyl derivatives, and α-ketoamides, form irreversible or slowly reversible bonds with the catalytic serine residue (Ser 135), producing long-lasting and high-affinity suppression of protease activity. In parallel, several classes of non-covalent, particularly allosteric, inhibitors have emerged as promising alternatives with improved specificity and reduced off-target reactivity. A complementary antiviral strategy involves the use of agonists of key innate immune sensors such as TLRs, RIG-I, and the cGAS–STING axis, which mediate the release of interferons (IFNs). This review brings together current knowledge on these two mechanistically distinct yet convergent approaches, highlighting how both can ultimately restrict flavivirus replication. Future opportunities involving modified peptide scaffolds, advanced delivery systems, and drug-repurposing strategies are finally discussed for the development of next-generation therapeutics against DENV and ZIKV. Full article