In‐Silico Screening, Molecular Dynamics, and DFT Analysis of ZINC and ChEMBL Library Compounds for SARS‐CoV‐2 Main Protease Inhibition

ChemistrySelect, Journal Year: 2025, Volume and Issue: 10(4)

Published: Jan. 1, 2025

Abstract Although COVID‐19 is no longer classified as a global emergency, the emergence of SARS‐CoV‐2 variants highlights urgent need for antiviral drug discovery. This study identifies potent inhibitors main protease, supporting future preparedness and advancing strategies. Using experimental drugs from ZINC ChEMBL libraries, systematic workflow combining SwissSimilarity‐based screening, molecular docking, dynamics (MD) simulations, density functional theory (DFT) calculations was employed robust candidate assessment. Five potential inhibitors, sharing 4‐(2‐pyrimidin‐4‐yl)‐morpholine motif, were identified. Among them, Apilimod, known its immunomodulatory properties, showed promising efficacy against viral replication in prior studies. Detailed interaction analyzed through 2.5 microseconds MD simulations (500 ns per complex), revealing critical insights into stability, binding modes, conformational drug‐protein complexes. MM/PBSA free energy further demonstrated Apilimod’s superior affinity compared to other candidates. These findings highlight therapeutic Apilimod structural analogs antivirals. By leveraging advanced computational techniques, this provides valuable combating addressing threats.

Language: Английский

Let’s Not Neglect Drug Discovery to Combat COVID-19: In Silico Study of the Anti-Cancer Compounds Flexible Heteroarotinoids as Candidate Inhibitors Against SARS-CoV-2 Proteins

OMICS A Journal of Integrative Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 10, 2025

The COVID-19 pandemic phase caused by the SARS-CoV-2 has ended, but emergence of new variants continues to threaten public health. health toolbox for is in need not only vaccines also drug discovery against virus, causative agent ongoing infections. We report here an silico molecular docking and dynamics study that uncovered interactions 26 flexible heteroarotinoids (FHT18), which are a class anti-cancer compounds, as potential inhibitors all 24 proteins. Of 624 docked complexes, 69 displayed binding energies between -9.0 -11.6 kcal/mol, indicating good strong affinities. At least five these compounds excellent affinities nonstructural protein 2, papain-like protease, 4 (Nsp4), proof-reading exoribonuclease, membrane protein, nucleocapsid protein. Structure-activity relationship (SAR) analyses results revealed urea linker place thiourea linker, enhanced hydrophobic side chains attached chromane unit, CF3 or OCF3 functional group benzene ring contributed increased Further, simulation best-docked complex FHT18-6c with Nsp4 remained stable at 200 ns, leading decreased structural fluctuations compactness site. In conclusion, deserves further translational research explore its repurposing potent candidate combat COVID-19. call continued efforts enrich

Language: Английский