{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:22Z","timestamp":1787028502840,"version":"build-2736575974"},"reference-count":96,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T00:00:00Z","timestamp":1676851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["91631304"],"award-info":[{"award-number":["91631304"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2022KF007"],"award-info":[{"award-number":["2022KF007"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"State Key Laboratory for Conservation and Utilization of Bio-Resources at Yunnan University","award":["91631304"],"award-info":[{"award-number":["91631304"]}]},{"name":"State Key Laboratory for Conservation and Utilization of Bio-Resources at Yunnan University","award":["2022KF007"],"award-info":[{"award-number":["2022KF007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The indispensable role of the SARS-CoV-2 main protease (Mpro) in the viral replication cycle and its dissimilarity to human proteases make Mpro a promising drug target. In order to identify the non-covalent Mpro inhibitors, we performed a comprehensive study using a combined computational strategy. We first screened the ZINC purchasable compound database using the pharmacophore model generated from the reference crystal structure of Mpro complexed with the inhibitor ML188. The hit compounds were then filtered by molecular docking and predicted parameters of drug-likeness and pharmacokinetics. The final molecular dynamics (MD) simulations identified three effective candidate inhibitors (ECIs) capable of maintaining binding within the substrate-binding cavity of Mpro. We further performed comparative analyses of the reference and effective complexes in terms of dynamics, thermodynamics, binding free energy (BFE), and interaction energies and modes. The results reveal that, when compared to the inter-molecular electrostatic forces\/interactions, the inter-molecular van der Waals (vdW) forces\/interactions are far more important in maintaining the association and determining the high affinity. Given the un-favorable effects of the inter-molecular electrostatic interactions\u2014association destabilization by the competitive hydrogen bond (HB) interactions and the reduced binding affinity arising from the un-compensable increase in the electrostatic desolvation penalty\u2014we suggest that enhancing the inter-molecular vdW interactions while avoiding introducing the deeply buried HBs may be a promising strategy in future inhibitor optimization.<\/jats:p>","DOI":"10.3390\/ijms24044237","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T02:07:44Z","timestamp":1676945264000},"page":"4237","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Identification of and Mechanistic Insights into SARS-CoV-2 Main Protease Non-Covalent Inhibitors: An In-Silico Study"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4467-4034","authenticated-orcid":false,"given":"Jian-Xin","family":"Shen","sequence":"first","affiliation":[{"name":"State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming 650091, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Wen","family":"Du","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming 650091, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Ling","family":"Xia","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming 650091, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9704-6571","authenticated-orcid":false,"given":"Zhi-Bi","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming 650091, China"},{"name":"Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Biomedical Engineering Research Center, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze-Fen","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming 650091, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Xin","family":"Fu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming 650091, China"},{"name":"Human Genetics Center and Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2023-4552","authenticated-orcid":false,"given":"Shu-Qun","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming 650091, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1002\/jmv.25678","article-title":"Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle","volume":"92","author":"Lu","year":"2020","journal-title":"J. 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