Integrated In Silico Discovery of Thymoquinone Analogs Targeting the Keap1–Nrf2 Pathway for Amyotrophic Lateral Sclerosis Therapy

Computational drug repurposing identifies flavoxate as a novel NLRP3 inflammasome inhibitor for Alzheimer’s disease therapy

Dual-site TAS2R14 binding by (-)-epicatechin gallate: A computational framework for neuroprotective drug repurposing.

Bitter taste receptors, particularly TAS2R14, are widely expressed in extraoral tissues, including the central nervous system, where they have been implicated in neuroinflammatory and neurodegenerative processes. Although numerous pharmacological and natural compounds have demonstrated therapeutic potential against neurodegenerative disorders, clinically effective disease-modifying therapies remain strikingly limited. TAS2R14 is a promising yet underexplored candidate target; however, its mechanistic role in neurodegenerative disorders remains poorly understood. Here, we conducted a structure-based virtual screening of 4138 FDA-approved drugs from the MedChemExpress database to identify potential TAS2R14 ligands for therapeutic repositioning. Top candidates were prioritized through a hierarchical molecular docking workflow and binding free-energy calculations (MM-GBSA), orthogonal GNINA validation, in silico ADMET assessment, followed by 500 ns molecular dynamics (MD) simulations to evaluate the persistence of predicted binding modes and ligand-associated conformational behavior at both extracellular and intracellular binding sites. The selected hits exhibited distinct predicted interaction profiles and conformational dynamics at the two independent binding sites. Among them, (-)-epicatechin gallate exhibited favorable interactions, persistent contact with key binding site residues, and comparatively limited conformational fluctuations at both sites, supporting its prioritization as a potential dual-site TAS2R14 binder. Furthermore, fexofenadine and ezetimibe showed favorable binding stability at the extracellular and intracellular sites, respectively. Hydrogen-bond analysis, principal component analysis, dynamic cross-correlation matrix analysis, and free-energy landscape mapping further revealed ligand-dependent differences in interaction networks and receptor conformational behavior. Notably, (-)-epicatechin gallate, fexofenadine, and ezetimibe exhibited greater predicted binding stability than the reference ligands flufenamic acid, cholesterol, and Comp28.1 throughout the 500 ns simulations. As this study is purely computational, experimental validation through receptor activation assays and relevant biological models will be required to determine whether the predicted binding interaction translates into functional modulation of TAS2R14 and therapeutic benefit. Nevertheless, these findings provide a computational foundation for prioritizing candidate TAS2R14 ligands and support future experimental studies to evaluate receptor activation, specificity, selectivity, and therapeutic efficacy, particularly for (-)-epicatechin gallate, in the context of TAS2R14-targeted neuroprotective drug repositioning.

Computational identification of natural phytochemicals as potential inhibitors of UBE2J1 causing ovarian cancer

Findings highlight Withaferin A as a promising natural inhibitor of UBE2J1 and provide a foundation for future experimental validation aimed at developing targeted therapies against ovarian cancer.

The Discovery of GSK3227634: A Potent Inhaled Inhibitor of the KEAP1/NRF2 Protein–Protein Interaction for the Treatment of Chronic Obstructive Pulmonary Disease

KEAP1 is the key regulator of the NRF2-mediated cytoprotective response and a target for pathologies involving oxidative stress. Compounds that covalently modify KEAP1 to activate NRF2 are clinically validated; however, their chemical reactivity may drive increased off–target activity. A more selective approach involves inhibition of the KEAP1-NRF2 protein–protein interaction as exemplified by our previous bis-aryl lead KI-696 (4). We now describe the lead optimization of the bis-aryl series that focused on increasing the population of the bioactive conformation of the free ligand to drive potency while optimizing overall physicochemical properties. This resulted in the discovery of GSK3227634 (5), an ultrahigh-affinity noncovalent inhibitor of KEAP1-NRF2 (surface plasmon resonance pKd = 10.9) and the first NRF2 activator to demonstrate target engagement and efficacy in preclinical models of oxidative stress via direct delivery to the lung. Compound 5 therefore represents a novel potential agent to treat lung diseases involving oxidative stress, such as chronic obstructive pulmonary disease.

Cannabidiol as a Promising Anti-Inflammatory Agent Targeting TYK2: Molecular Docking and Dynamic Simulation Approaches for Therapeutic Applications in Multiple Sclerosis.

INTRODUCTION Multiple sclerosis (MS) involves chronic inflammation driven by dysregulation of the JAK-STAT pathway. This study aimed to evaluate the potential interaction of natural cannabinoids with TYK2, with a focus on cannabidiol (CBD), using computational in silico approaches. METHODS A combined molecular docking and molecular dynamics (MD) workflow was used. Cannabinoid ligands and the TYK2 structure (JH2 domain) were prepared and docked in MOE, followed by 20 ns MD simulations under NVT and NPT conditions in GROMACS. Complex stability and ligand-protein interactions were analysed. RESULTS CBD showed a competitive docking score (-7.31 kcal/mol) and a refined RMSD of 0.9198 Å. MD simulations revealed a stable CBD-TYK2 complex, with RMSD fluctuations of 0.15-0.20 nm, which were lower than those observed for the reference inhibitor, deucravacitinib. RMSF analysis revealed a slight increase in local flexibility in specific regions without affecting the overall stability of the protein. The radius of gyration remained stable throughout the simulation, indicating that the protein's compactness was preserved. Hydrogen bond analysis showed fewer but transient interactions for CBD, consistent with a binding mode dominated by hydrophobic interactions. DISCUSSION These computational results suggest that CBD interacts stably with TYK2 through a distinct binding mode compared to the reference inhibitor, deucravacitinib, while maintaining the structural integrity of the protein. CONCLUSION CBD showed a stable predicted interaction with TYK2, supporting its potential as a candidate for further in vitro and in vivo studies in the context of MS-related inflammation.

Integrated identification and validation of HSP90AA1 as a therapeutic target of Astragalus membranaceus in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder lacking effective disease-modifying therapies. Astragalus membranaceus (AM) has shown potential neuroprotective effects, but its underlying mechanisms remain incompletely understood. In this study, a meta-analysis, network pharmacology, molecular simulation, and experimental validation were integrated to investigate the therapeutic potential of AM in AD. Meta-analysis of three randomized controlled trials showed that AM significantly improved Clinical Dementia Rating-Sum of Boxes scores, whereas no significant differences were observed for MMSE, memory-related outcomes, or SNSB-D. Network pharmacology identified 350 overlapping targets between AM and AD, with enrichment in pathways related to PI3K-Akt signaling and neural ligand-receptor interactions. HSP90AA1, PIK3CA, and ESR1 were identified as hub targets. Molecular docking predicted stable binding of astragaloside VII to the ATP-binding pocket of HSP90AA1 (-8.9 kcal/mol), which was further supported by molecular dynamics simulation and MM/PBSA analysis (-63.13 ± 4.82 kcal/mol). In Aβ-induced SH-SY5Y cells, astragaloside VII improved cell viability, reduced inflammatory cytokine production and the Aβ42/Aβ40 ratio, restored mitochondrial membrane potential, decreased reactive oxygen species accumulation, alleviated Tau hyperphosphorylation, and increased PSD95 expression. These effects were markedly attenuated following HSP90AA1 knockdown. Collectively, these findings suggest that AM may exert neuroprotective effects through HSP90AA1-associated regulation of multiple AD-related pathological processes and provide preliminary evidence supporting further mechanistic and translational studies.