{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:38:29Z","timestamp":1792607909639,"version":"4.5.0"},"reference-count":112,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T00:00:00Z","timestamp":1739145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"high-caliber talent of a Tuojiang scholar from Shandong Jiaotong University","award":["TJXZ202204"],"award-info":[{"award-number":["TJXZ202204"]}]},{"name":"high-caliber talent of a Tuojiang scholar from Shandong Jiaotong University","award":["ZR2021MA069"],"award-info":[{"award-number":["ZR2021MA069"]}]},{"name":"high-caliber talent of a Tuojiang scholar from Shandong Jiaotong University","award":["2019GGX102050"],"award-info":[{"award-number":["2019GGX102050"]}]},{"name":"Natural Science Foundation of Shandong Province","award":["TJXZ202204"],"award-info":[{"award-number":["TJXZ202204"]}]},{"name":"Natural Science Foundation of Shandong Province","award":["ZR2021MA069"],"award-info":[{"award-number":["ZR2021MA069"]}]},{"name":"Natural Science Foundation of Shandong Province","award":["2019GGX102050"],"award-info":[{"award-number":["2019GGX102050"]}]},{"name":"Key Research and Development Project of Shandong province","award":["TJXZ202204"],"award-info":[{"award-number":["TJXZ202204"]}]},{"name":"Key Research and Development Project of Shandong province","award":["ZR2021MA069"],"award-info":[{"award-number":["ZR2021MA069"]}]},{"name":"Key Research and Development Project of Shandong province","award":["2019GGX102050"],"award-info":[{"award-number":["2019GGX102050"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as 3CLpro, is crucial in the virus\u2019s life cycle and plays a pivotal role in COVID-19. Understanding how small molecules inhibit 3CLpro\u2019s activity is vital for developing anti-COVID-19 therapeutics. To this end, we employed Gaussian accelerated molecular dynamics (GaMD) simulations to enhance the sampling of 3CLpro conformations and conducted correlation network analysis (CNA) to explore the interactions between different structural domains. Our findings indicate that a CNA-identified node in domain II of 3CLpro acts as a conduit, transferring conformational changes from the catalytic regions in domains I and II, triggered by the binding of inhibitors (7YY, 7XB, and Y6G), to domain III, thereby modulating 3CLpro\u2019s activity. Normal mode analysis (NMA) and principal component analysis (PCA) revealed that inhibitor binding affects the structural flexibility and collective movements of the catalytic sites and domain III, influencing 3CLpro\u2019s function. The binding free energies, predicted by both MM-GBSA and QM\/MM-GBSA methods, showed a high correlation with experimental data, validating the reliability of our analyses. Furthermore, residues L27, H41, C44, S46, M49, N142, G143, S144, C145, H163, H164, M165, and E166, identified through residue-based free energy decomposition, present promising targets for the design of anti-COVID-19 drugs and could facilitate the development of clinically effective 3CLpro inhibitors.<\/jats:p>","DOI":"10.3390\/molecules30040805","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T11:08:51Z","timestamp":1739358531000},"page":"805","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Identifying Inhibitor-SARS-CoV2-3CLpro Binding Mechanism Through Molecular Docking, GaMD Simulations, Correlation Network Analysis and MM-GBSA Calculations"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1558-4398","authenticated-orcid":false,"given":"Jianzhong","family":"Chen","sequence":"first","affiliation":[{"name":"School of Science, Shandong Jiaotong University, Jinan 250357, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8635-3635","authenticated-orcid":false,"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Science, Shandong Jiaotong University, Jinan 250357, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0899-123X","authenticated-orcid":false,"given":"Wanchun","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Science, Shandong Jiaotong University, Jinan 250357, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Science, Shandong Jiaotong University, Jinan 250357, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Science, Shandong Jiaotong University, Jinan 250357, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,10]]},"reference":[{"key":"ref_1","unstructured":"WHO (2024, January 12). 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