Missense variants in the methyl-CpG-binding domain (MBD) of MeCP2 are associated with Rett syndrome, yet their molecular effects on protein stability and DNA recognition remain incompletely understood. Here, we integrated structural mapping, energetic prediction, molecular dynamics (MD) simulations, and virtual screening to investigate 80 ClinVar-reported MeCP2 MBD missense variants associated with Rett syndrome and mapped to structurally resolved MBD residues. The variants were distributed mainly across the protein interior and protein–DNA interface. Energy predictions suggested that most variants were destabilizing or produced less favorable MeCP2–DNA binding energetics. MD simulations of eight representative variants revealed mutation-specific changes in conformational dynamics, local flexibility, hydrogen-bond networks, and binding energetics. A two-stage virtual-screening workflow targeting the Arg133Cys-centered MeCP2–DNA interface prioritized five FDA-approved compounds. Subsequent MD simulations further prioritized DB00694 and DB06237 based on retention at the target interface, increased numbers of persistent protein–DNA hydrogen bonds, and more favorable MeCP2–DNA interaction energetics. Overall, these results provide a molecular framework for understanding mutation-specific perturbations of MeCP2–DNA recognition and prioritize compounds for subsequent experimental evaluation.
Oxidative stress-mediated cellular damage is closely associated with the development of several chronic disorders, highlighting the importance of identifying efficient antioxidant molecules. In this study, the antioxidant potential of four structurally different flavonoids namely Kaempferol (MBFL-1), Sudachitin (MBFL-2), Melodorone A (MBFL-3) and Desmoscochinflavone A (MBFL-4) was explained by using integrated computational approach including density functional theory (DFT), molecular docking, molecular dynamics (MD) simulation and MM/PBSA analysis. The DFT calculations revealed significance of hydroxyl group positioning and conjugation pattern in free radical scavenging efficiency via the HAT, SPLET and SET-PT mechanisms. Among them, MBFL-4 exhibited most favoirable antioxidant profile, characterized by the lowest BDE value of 79.21 kcal/mol for HAT mechanism and lowest PA value of 36.02 kcal/mol for initial step of SPLET pathway. The docking analysis of ROS generating enzyme, Xanthine oxidase (PDB ID: 3NVY) showed favorable interactions of MBFL-4 with binding affinities of -8.35 kcal/mol which is consistent with its superior radical scavenging behavior. The studied flavonoids also showed good binding interactions with Keap1 demonstrating binding energies < -6.0 kcal/mol, which might indicate that these flavonoids could be able to modulate the binding interactions of the Nrf2 antioxidant defense pathway. Moreover, 100 ns MD simulation with target protein 3NVY presented MBFL-4 as the most stable and energetically favorable complex with a binding free energy of -17.38 kcal/mol. This highlighting the contribution of enzymatic/signalling pathway modulation in controlling oxidative stress along with free radical scavenging activity, attributed to appropriate hydroxyl configuration and conjugation pattern.
Multidrug-resistant Staphylococcus aureus represents a major clinical challenge because of the increasing prevalence of antimicrobial resistance and efflux-mediated resistance mechanisms. The MepR-MepA regulatory system is involved in the control of multidrug efflux in S. aureus, making MepR a relevant target for investigating compounds capable of modulating this regulatory system. In the present study, an integrated genomic and structure-based computational workflow was applied to S. aureus strain M48 to characterize antimicrobial resistance determinants and prioritize potential MepR-binding compounds. Whole-genome analysis using the Comprehensive Antibiotic Resistance Database (CARD) and Resistance Gene Identifier (RGI) identified the resistance-associated genetic repertoire of the strain, followed by comparative analysis of selected determinants. The MepR structure was evaluated using structural modelling and experimental structural information, and candidate binding regions were investigated through virtual screening and molecular docking. Adozelesin and zoliflodacin were prioritized based on their predicted interactions with MepR. Molecular-dynamics simulations were subsequently used to examine the structural behavior of the resulting complexes, while complementary physicochemical, pharmacokinetic, drug-likeness, and toxicity predictions were performed to characterize their computational ADMET profiles. Adozelesin showed a more favorable predicted docking score, whereas zoliflodacin displayed comparatively lower structural fluctuations and more persistent protein-ligand interactions during the simulated trajectory. These findings identify adozelesin and zoliflodacin as computationally prioritized MepR-binding candidates for further investigation. Importantly, the present study does not establish MepR inhibition or demonstrate functional effects on MepR-mediated repression or mepA expression. Experimental binding, DNA-binding, transcriptional, and antibacterial studies are required to determine the biological significance of the predicted interactions.
Dengue virus (DENV) NS5's RdRp domain is a conserved and functionally necessary enzyme, making it an interesting antiviral target. This study examined Carica papaya flavonoids' efficacy in inhibiting DENV-RdRp's allosteric binding domain utilizing structure-based in silico methods. Eight flavonoids were evaluated for RdRp enzyme binding affinity using molecular dynamics simulations, principal component analysis, and free energy landscapes. The molecular simulation studies predicted the formation of stable protein-ligand complex structures in a biological system. Further protein-ligand structure dissociation and unbinding energetics were quantified using SMD simulations with umbrella sampling. By deriving free energy profiles, all eight RdRp-flavonoid complexes showed thermodynamic feasibility for protein-ligand binding with neohesperidin, manghaslin, and isoquercetin complexes having binding energies of -17.35 kcal & sdot;mol(-1), -16.52 kcal & sdot;mol(-1), and -16.04 kcal & sdot;mol(-1), respectively. These results were aligned with the MD and post-MD MMGBSA binding free energy calculations. Thus, we successfully identified and analyzed papaya flavonoid-based natural scaffolds that target DENV-RdRp using advanced molecular simulation methods.
The papain-like protease (PL pro ) of severe respiratory syndrome coronavirus 2 (SARS-CoV-2) is a promising therapeutic target owing to its vital role in viral polyprotein processing and modulation of host immune responses. Therefore, in the present work, a library of thiazole-benzamide analogues 8a-l incorporating (R)-1-(naphthalen-1-yl)ethyl amide moiety was designed, synthesized and evaluated for inhibitory activity against SARS-CoV-2. Among the synthesized compounds, 4-chloropyridin-3-yl based derivative 8f displayed the most potent PL pro inhibition with an IC50 value of 1.17 ± 0.13 µM, followed by the derivative 8e (IC 50 = 1.38 ± 0.18 µM) and 8g (I C50 = 1.53 ± 0.30 µM) possessing 6-methylpyridin-2-yl and isoquinolin-1-yl groups, respectively. All these three compounds 8f showed lower IC 50 values compared to the standard inhibitor GRL0617 (IC 50 = 2.65 ± 1.10 µM). While the observed weaker potency of several five membered heteroaromatic analogues clearly demonstrated the dependence of the positioning of substituents and heteroaromatic ring selection for modulation of PLpro inhibition. Molecular docking against SARS-CoV-2 PLpro (PDB ID: 7CMD) revealed favorable predicted binding affinities for 8f (−8.337 kcal/mol), 8e (−8.099 kcal/mol), and 8g (−7.732 kcal/mol) compared with GRL0617 (−7.218 kcal/mol). Notably, compound 8f established three predicted hydrogen bonds with GLN269, ASP164, and TYR273, together with and hydrophobic interactions involving TYR268, PRO247, and PRO248, supporting its favorable accommodation within the PLpro binding pocket. Density functional theory calculations at the B3LYP/6-311G(d,p) level demonstrated that 8f possessed the smallest HOMO–LUMO energy gap (3.80 eV) among the investigated derivatives, along with the highest global softness (0.263 eV −1 ) and electrophilicity index (3.34 eV), indicating comparatively greater electronic polarizability and charge-transfer propensity. Molecular electrostatic potential analysis further identified electron-rich carbonyl and heterocyclic regions as potential sites for intermolecular interactions. ADMET predictions indicated that 8f exhibited the highest predicted PAMPA permeability (0.778) among the evaluated derivatives; however, high lipophilicity, limited aqueous solubility, and potential metabolic and toxicity liabilities highlighted the need for further structural optimization and experimental safety assessment. Collectively, the experimental and computational findings identify 8f as a promising lead compound and establish the thiazolebenzamide framework as a potential platform for developing novel SARS-CoV-2 PLpro inhibitors.
