{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T10:31:17Z","timestamp":1787049077952,"version":"build-2736575974"},"reference-count":246,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["CPRR23031081848"],"award-info":[{"award-number":["CPRR23031081848"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The SARS-CoV-2 pandemic has significantly impacted global health, politics, medicine, finance, and society. Since 2020, various mutations have been reported, leading to drug resistance in current treatments against different SARS-CoV-2 strains and a drastic increase in cases of long-COVID. This situation underscores the urgent need to develop targeted and effective drugs to combat the spread of SARS-CoV-2 strains and their mutants, manage long-COVID symptoms and prepare for future pandemics. Currently, the treatment of SARS-CoV-2 focuses on targeting the virus\u2019s entry and replication mechanisms to disrupt its life cycle. This review examines approved drugs, clinical candidates, and inhibitors under development, along with their bioassay data, while highlighting associated challenges. It illustrates how inhibitors bind to active sites, providing insights and emphasizing the importance of in silico studies, such as molecular docking, molecular dynamics simulation, FEP+, WaterMap, and quantitative structure\u2013activity relationship (QSAR) analyses, and their correlation with experimental studies in expediting the drug discovery process. The review aims to provide researchers with insights into the gaps that need to be addressed concerning mutations affecting viral entry and to prepare for future pandemics.<\/jats:p>","DOI":"10.3390\/molecules31162877","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T10:22:52Z","timestamp":1787048572000},"page":"2877","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Recent Advances in the Design of Inhibitors Targeting the Viral Entry and Replication of the SARS-CoV-2 Virus, Driven by In Silico Approaches"],"prefix":"10.3390","volume":"31","author":[{"given":"Phumelele","family":"Nodola","sequence":"first","affiliation":[{"name":"Department of Chemical and Physical Sciences, Faculty of Natural Sciences, iYunivesithi Walter Sisulu (iWS), Private Bag X01, Mthatha 5099, Eastern Cape, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patience S. S.","family":"Molefe","sequence":"additional","affiliation":[{"name":"Department of Chemical and Physical Sciences, Faculty of Natural Sciences, iYunivesithi Walter Sisulu (iWS), Private Bag X01, Mthatha 5099, Eastern Cape, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Potlaki F.","family":"Tseki","sequence":"additional","affiliation":[{"name":"Department of Chemical and Physical Sciences, Faculty of Natural Sciences, iYunivesithi Walter Sisulu (iWS), Private Bag X01, Mthatha 5099, Eastern Cape, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Njabulo J.","family":"Gumede","sequence":"additional","affiliation":[{"name":"Department of Chemical and Physical Sciences, Faculty of Natural Sciences, iYunivesithi Walter Sisulu (iWS), Private Bag X01, Mthatha 5099, Eastern Cape, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Katte, R.H., Ao, Y., Xu, W., Han, Y., Zhong, G., Ghimire, D., Florence, J., Tucker, T.A., and Lu, M. 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