{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T10:47:39Z","timestamp":1792061259471,"version":"4.4.0"},"reference-count":62,"publisher":"American Chemical Society (ACS)","issue":"20","license":[{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001843","name":"Science and Engineering Research Board","doi-asserted-by":"publisher","award":["DST\/2022\/00489"],"award-info":[{"award-number":["DST\/2022\/00489"]}],"id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001843","name":"Science and Engineering Research Board","doi-asserted-by":"publisher","award":["EEQ\/2022\/000571"],"award-info":[{"award-number":["EEQ\/2022\/000571"]}],"id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Drug development against RNA viruses is challenging due to continuously emerging mutational variants. RNA-dependent RNA polymerases (RdRp) of most RNA viruses are conserved in their catalytic and allosteric sites, making them a promising target for drug development and repurposing. Some RdRp allosteric inhibitors of Hepatitis C Virus (HCV) have undergone Phase I and II clinical trials. Aiming to rationally design RdRp inhibitors to combat emerging and life-threatening RNA viruses, we explored the binding modes and mechanisms of HCV RdRp allosteric inhibitors against HCV and SARS-CoV-2 RdRps through molecular docking, molecular dynamics (MD), and well-tempered metadynamic (WT-MD) simulations. Twelve allosteric inhibitors of HCV were screened based on their binding free energy profile through WT-MD simulations to understand the binding modes and their inhibitory mechanisms. Our results suggest that these inhibitors have a higher binding affinity toward HCV RdRp and a weaker binding affinity toward different allosteric sites of SARS-CoV-2 RdRp. WT-MD simulations provided details about the binding modes of these inhibitors in HCV and SARS-CoV-2 RdRp. The preliminary functional group modifications of lead molecules identified through WT-MD showed improved binding energy toward SARS-CoV-2 RdRp. WT-MD simulations provide insights into the binding modes of these inhibitors in HCV and SARS-CoV-2 RdRp and also provide structural insights, leads, and principles for designing effective allosteric inhibitors to combat future SARS-CoV-2 and other RNA virus outbreaks.<\/jats:p>","DOI":"10.1021\/acs.jcim.5c01458","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T23:51:47Z","timestamp":1760572307000},"page":"11107-11122","source":"Crossref","is-referenced-by-count":1,"title":["Well-Tempered Metadynamic\nSimulations Provide Insights\nand Leads for Designing Effective Allosteric Inhibitors against SARS-CoV-2\nRNA-Dependent RNA Polymerase"],"prefix":"10.1021","volume":"65","author":[{"given":"Wilbee D.","family":"Sasikala","sequence":"first","affiliation":[{"name":"BRIC-Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB) , , , ,","place":["Thiruvananthapuram, Kerala, India, 695014"]},{"name":"Govt. Medical College , , , ,","place":["Thiruvananthapuram, Kerala, India, 695011"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6160-4586","authenticated-orcid":true,"given":"Reman Kumar","family":"Singh","sequence":"additional","affiliation":[{"name":"St. Xavier\u2019s College , , , ,","place":["Ranchi, Jharkhand, India, 834001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2255-5966","authenticated-orcid":true,"given":"Kathiresan","family":"Natarajan","sequence":"additional","affiliation":[{"name":"BRIC-Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB) , , , ,","place":["Thiruvananthapuram, Kerala, India, 695014"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"key":"2026101506061167700_cit1","doi-asserted-by":"publisher","first-page":"102253","DOI":"10.1016\/j.coi.2022.102253","article-title":"Oncogenic viruses, cancer biology, and innate immunity","volume":"78","author":"White","year":"2022","journal-title":"Curr. 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