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M. Keck Foundation","award":["2021YFF1200404","2021YFA1201200","U1967217","NCTIB2022HS02010","226-2022-00043","226-2022-00192","ZJZX2020014","P22KN00272","SN-ZJU-SIAS-003","BR-ZJU-SIAS-001","2019\u20132022"],"award-info":[{"award-number":["2021YFF1200404","2021YFA1201200","U1967217","NCTIB2022HS02010","226-2022-00043","226-2022-00192","ZJZX2020014","P22KN00272","SN-ZJU-SIAS-003","BR-ZJU-SIAS-001","2019\u20132022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The emergence of the recent pandemic causing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an alarming situation worldwide. It also prompted extensive research on drug repurposing to find a potential treatment for SARS-CoV-2 infection. An active metabolite of the hyperlipidemic drug fenofibrate (also called fenofibric acid or FA) was found to destabilize the receptor-binding domain (RBD) of the viral spike protein and therefore inhibit its binding to human angiotensin-converting enzyme 2 (hACE2) receptor. Despite being considered as a potential drug candidate for SARS-CoV-2, FA\u2019s inhibitory mechanism remains to be elucidated. We used molecular dynamics (MD) simulations to investigate the binding of FA to the RBD of the SARS-CoV-2 spike protein and revealed a potential cryptic FA binding site. Free energy calculations were performed for different FA-bound RBD complexes. The results suggest that the interaction of FA with the cryptic binding site of RBD alters the conformation of the binding loop of RBD and effectively reduces its binding affinity towards ACE2. Our study provides new insights for the design of SARS-CoV-2 inhibitors targeting cryptic sites on the RBD of SARS-CoV-2.<\/jats:p>","DOI":"10.3390\/biom13020359","type":"journal-article","created":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T02:16:01Z","timestamp":1676340961000},"page":"359","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel Inhibitory Role of Fenofibric Acid by Targeting Cryptic Site on the RBD of SARS-CoV-2"],"prefix":"10.3390","volume":"13","author":[{"given":"Jianxiang","family":"Huang","sequence":"first","affiliation":[{"name":"Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, Hangzhou 310027, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3705-1835","authenticated-orcid":false,"given":"Kevin C.","family":"Chan","sequence":"additional","affiliation":[{"name":"Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, Hangzhou 310027, China"},{"name":"Shanghai Institute for Advanced Study, Zhejiang University, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8624-5591","authenticated-orcid":false,"given":"Ruhong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, Hangzhou 310027, China"},{"name":"Shanghai Institute for Advanced Study, Zhejiang University, Shanghai 201203, China"},{"name":"The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China"},{"name":"Department of Chemistry, Colombia University, New York, NY 10027, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/s41586-020-2798-3","article-title":"SARS-CoV-2 vaccines in development","volume":"586","author":"Krammer","year":"2020","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/s41392-021-00796-w","article-title":"The way of SARS-CoV-2 vaccine development: Success and challenges","volume":"6","author":"Dong","year":"2021","journal-title":"Signal Transduct. 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