{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:59:28Z","timestamp":1791824368097,"version":"4.3.4"},"reference-count":90,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,11]],"date-time":"2025-01-11T00:00:00Z","timestamp":1736553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"State Key Laboratory for Conservation and Utilization of Bio-Resources at Yunnan University","award":["2024KF003"],"award-info":[{"award-number":["2024KF003"]}]},{"name":"State Key Laboratory for Conservation and Utilization of Bio-Resources at Yunnan University","award":["2023YFD1400400"],"award-info":[{"award-number":["2023YFD1400400"]}]},{"name":"National Key R&amp;D Program of China","award":["2024KF003"],"award-info":[{"award-number":["2024KF003"]}]},{"name":"National Key R&amp;D Program of China","award":["2023YFD1400400"],"award-info":[{"award-number":["2023YFD1400400"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The human transmembrane protease, serine 2 (TMPRSS2), essential for SARS-CoV-2 entry, is a key antiviral target. Here, we computationally profiled the TMPRSS2-binding affinities of 15 antiviral compounds. Molecular dynamics (MD) simulations for the docked complexes revealed that three compounds exited the substrate-binding cavity (SBC), suggesting noncompetitive inhibition. Of the remaining compounds, five charged ones exhibited reduced binding stability due to competing electrostatic interactions and increased solvent exposure, while seven neutral compounds showed stronger binding affinity driven by van der Waals (vdW) interactions compensating for unfavorable electrostatic effects (including electrostatic interactions and desolvation penalties). Positive and negative hotspot residues were identified as uncharged and charged, respectively, both lining the SBC. Despite forming diverse interactions with compounds, the burial of positive hotspots led to strong vdW interactions that overcompensated for unfavorable electrostatic effects, whereas negative hotspots incurred high desolvation penalties, negating any favorable contributions. Charged residues at the SBC\u2019s outer rim can reduce binding affinity significantly when forming hydrogen bonds or salt bridges. These findings underscore the importance of enhancing vdW interactions with uncharged residues and minimizing the unfavorable electrostatic effects of charged residues, providing valuable insights for designing effective TMPRSS2 inhibitors.<\/jats:p>","DOI":"10.3390\/ijms26020587","type":"journal-article","created":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T07:40:08Z","timestamp":1736754008000},"page":"587","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dissecting the Binding Affinity of Anti-SARS-CoV-2 Compounds to Human Transmembrane Protease, Serine 2: A Computational Study"],"prefix":"10.3390","volume":"26","author":[{"given":"Yue-Hui","family":"Shi","sequence":"first","affiliation":[{"name":"State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and School of Life Sciences, Yunnan University, Kunming 650091, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4467-4034","authenticated-orcid":false,"given":"Jian-Xin","family":"Shen","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and School of Life Sciences, Yunnan University, Kunming 650091, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Tao","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and 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 and 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":"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":"Yun-Xin","family":"Fu","sequence":"additional","affiliation":[{"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"}]},{"given":"Ke-Qin","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and School of Life Sciences, Yunnan University, Kunming 650091, China"}],"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 and School of Life Sciences, Yunnan University, Kunming 650091, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1056\/NEJMoa2001017","article-title":"A novel coronavirus from patients with pneumonia in China, 2019","volume":"382","author":"Zhu","year":"2020","journal-title":"N. 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