Machine Learning-Guided Screening and Molecular Docking for Proposing Naturally Derived Drug Candidates Against MERS-CoV 3CL Protease

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 3047 - 3047

Published: March 26, 2025

In this study, we utilized machine learning techniques to identify potential inhibitors of the MERS-CoV 3CL protease. Among models evaluated, Random Forest (RF) algorithm exhibited highest predictive performance, achieving an accuracy 0.97, ROC-AUC score 0.98, and F1-score 0.98. Following model validation, applied it a dataset 14,194 naturally occurring compounds from PubChem. The top-ranked were subsequently subjected molecular docking, which identified Perenniporide B, Phellifuropyranone A, Terrestrol G as most promising candidates, with binding energies -9.17, -9.08, -8.71 kcal/mol, respectively. These formed strong interactions key catalytic residues, suggesting significant inhibitory against viral Furthermore, dynamics simulations confirmed their stability within active site, reinforcing viability antiviral agents. This study demonstrates effectiveness integrating modeling accelerate discovery therapeutic candidates emerging threats.

Language: Английский

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S-nitrosylation of EZH2 alters PRC2 assembly, methyltransferase activity, and EZH2 stability to maintain endothelial homeostasis

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 27, 2025

Abstract Nitric oxide (NO), a versatile bio-active molecule modulates cellular functions through diverse mechanisms including S-nitrosylation of proteins. Herein, we report selected cysteine residues EZH2 in endothelial cells, which interplays with its stability and functions. We detect significant reduction H3K27me3 upon as contributed by the early dissociation SUZ12 from PRC2. Moreover, causes cytosolic translocation, ubiquitination, degradation. Further analysis reveal 329 induces instability, whereas 700 abrogates catalytic activity. further show that S-nitrosylation-dependent regulation maintains homeostasis both physiological pathological settings. Molecular dynamics simulation reveals inability to efficiently bind SAL domain S-nitrosylation. Taken together, our study reports associated PRC2 complex, thereby influencing epigenetics homeostasis.

Language: Английский

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Development of newer generation Vascular endothelial growth factor Receptor-2 Inhibitors: Pharmacophore based design, virtual Screening, molecular Docking, molecular dynamic Simulation, and DFT analyses

Journal of King Saud University - Science, Journal Year: 2024, Volume and Issue: 36(8), P. 103285 - 103285

Published: June 5, 2024

Vascular Endothelial Growth Factor (VEGF) has a greater impact on carcinogenesis, and it is the most significant receptor in mediating mutagenesis permeability of endothelial cells. Here, we report identification potential VEGFR-2 inhibitors as new putative anti-cancer agents. In this regard, pharmacophore model was generated, considering established potent VEGFR2 inhibitors. This further applied for virtual screening ZINC database feature-based design another eight molecules (B1–B8). Examining these using sequential computational approaches including molecular docking, dynamic simulation, DFT analysis leads to compounds B3, B5, B7 that showed better binding affinity, stability, interaction mechanisms concerning reference control, Sorafenib. Further, Lipinski rule filters ADMET support selected drug candidates subjected experimental validation.

Language: Английский

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Aptamer biosensor design for the detection of endocrine-disrupting chemicals small organic molecules using novel bioinformatics methods

Journal of Molecular Graphics and Modelling, Journal Year: 2024, Volume and Issue: 131, P. 108785 - 108785

Published: May 2, 2024

Language: Английский

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Unlocking the Immunomodulatory Potential of Rosmarinic Acid Isolated from Punica granatum L. Using Bioactivity-Guided Approach: In Silico, In Vitro, and In Vivo Approaches

Current Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 31(36), P. 5969 - 5988

Published: March 6, 2024

L. is well-known for its multifaceted therapeutic potential, including anti-inflammatory and immunomodulatory activities.

Language: Английский

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S-nitrosylation of EZH2 at C329 and C700 interplay with PRC2 complex assembly, methyltransferase activity, and EZH2 stability to regulate endothelial functions

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 8, 2024

ABSTRACT Nitric oxide (NO), a versatile bio-active molecule modulates cellular function through diverse mechanisms including S-nitrosylation of proteins. However, the role this post-translational modification in regulating epigenetic pathways was very limitedly explored. Herein, we report that NO causes selected cysteine residues EZH2 endothelial cells (EC) resulting SUZ12 dissociation from bound PRC2 complex, reduced methyltransferase activity, and diminished nuclear localization eventually hampering its stability. We detected significant reduction H3K27me3 upon exposure to as contributed by early complex. Longer donors caused cytosolic translocation, ubiquitination, further degradation primarily autophagosome-lysosome pathway. Through silico prediction analysis site-directed mutagenesis assay, identified three namely at locations 260, 329, 700 determined 329 induced instability while abrogated EZH2’s catalytic activity. A double mutant containing mutations Cysteine remained undeterred exposure. Furthermore, reinforcing exposed EC use an inhibitor demethylase, confirmed contribution EZH2-H3K27me3 axis defining NO-mediated regulation gene expression migration. Molecular dynamics simulation study revealed SUZ12’s inability efficiently binding SAL domain C329 C700. Taken together, our for first-time reports dependent associated complex –influences homeostasis.

Language: Английский

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