Journal of molecular modeling · 2025
Feasibility of the inhibitor development for SARS-CoV-2: a systematic approach for drug design.
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Sun Guangzhou, Shi Quanshan, Song Yuting, Cheng Dazhi, Jiang Yu, Hu Dongling, Yue Xinru, Yu Wentong, Shi Xiaodong, Hu Jianping
Аннотация
CONTEXT: The main protease (Mpro) of SARS-CoV-2 is highly conserved with low variability. It plays a key role in viral replication, making it a target for COVID-19 treatment. Currently, drugs like Paxlovid have significant side effects and high costs, so new alternatives are urgently needed.
METHODS: In this work, a medicine and food homology herbal drugs (MF-HHD) database is constructed, followed by a multi-scale and high-precision screening with various virtual screening techniques (ligand-based pharmacophore screening, Vina-based screening, and drug-forming, prescription-based screening). Quercetin was identified as a potent Mpro inhibitor through multi-stage virtual screening. Molecular dynamics simulations (500 ns) revealed its binding mechanism and stabilization effects on Mpro. The results revealed that upon binding, the inhibitor interacted with H41, H164, M165, L167, P168, D187, R188, Q189, and Q192 and altered the hydrogen bonding network between Mpro and the solvent allowing the inhibitor to bind the active pocket. Free energy landscape (FEL) and conformational clustering analysis showed that Mpro undergoes significant conformational changes when bound to quercetin. In this way, a complete drug screening chain will be used to search for potential Mpro inhibitors and obtain computationally validated candidate that can for experimental evaluation COVID-19.
METHODS: In this work, a medicine and food homology herbal drugs (MF-HHD) database is constructed, followed by a multi-scale and high-precision screening with various virtual screening techniques (ligand-based pharmacophore screening, Vina-based screening, and drug-forming, prescription-based screening). Quercetin was identified as a potent Mpro inhibitor through multi-stage virtual screening. Molecular dynamics simulations (500 ns) revealed its binding mechanism and stabilization effects on Mpro. The results revealed that upon binding, the inhibitor interacted with H41, H164, M165, L167, P168, D187, R188, Q189, and Q192 and altered the hydrogen bonding network between Mpro and the solvent allowing the inhibitor to bind the active pocket. Free energy landscape (FEL) and conformational clustering analysis showed that Mpro undergoes significant conformational changes when bound to quercetin. In this way, a complete drug screening chain will be used to search for potential Mpro inhibitors and obtain computationally validated candidate that can for experimental evaluation COVID-19.