{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:02:06Z","timestamp":1771372926086,"version":"3.50.1"},"reference-count":62,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T00:00:00Z","timestamp":1677628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DST-SERB","award":["YSS\/2015\/000158"],"award-info":[{"award-number":["YSS\/2015\/000158"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>The development of potent non-nucleoside inhibitors (NNIs) could be an alternate strategy to combating infectious bovine viral diarrhea virus (BVDV), other than the traditional vaccination. RNA-dependent RNA polymerase (RdRp) is an essential enzyme for viral replication; therefore, it is one of the primary targets for countermeasures against infectious diseases. The reported NNIs, belonging to the classes of quinolines (2h: imidazo[4,5-g]quinolines and 5m: pyrido[2,3-g] quinoxalines), displayed activity in cell-based and enzyme-based assays. Nevertheless, the RdRp binding site and microscopic mechanistic action are still elusive, and can be explored at a molecular level. Here, we employed a varied computational arsenal, including conventional and accelerated methods, to identify quinoline compounds\u2019 most likely binding sites. Our study revealed A392 and I261 as the mutations that can render RdRp resistant against quinoline compounds. In particular, for ligand 2h, mutation of A392E is the most probable mutation. The loop L1 and linker of the fingertip is recognized as a pivotal structural determinant for the stability and escape of quinoline compounds. Overall, this work demonstrates that the quinoline inhibitors bind at the template entrance channel, which is governed by conformational dynamics of interactions with loops and linker residues, and reveals structural and mechanistic insights into inhibition phenomena, for the discovery of improved antivirals.<\/jats:p>","DOI":"10.3390\/ph16030376","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T02:10:59Z","timestamp":1677723059000},"page":"376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Template Entrance Channel as Possible Allosteric Inhibition and Resistance Site for Quinolines Tricyclic Derivatives in RNA Dependent RNA Polymerase of Bovine Viral Diarrhea Virus"],"prefix":"10.3390","volume":"16","author":[{"given":"Mitul","family":"Srivastava","sequence":"first","affiliation":[{"name":"Computational Biophysics and CADD Group, Computational and Mathematical Biology Center, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad 121001, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lovika","family":"Mittal","sequence":"additional","affiliation":[{"name":"Computational Biophysics and CADD Group, Computational and Mathematical Biology Center, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad 121001, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6985-4686","authenticated-orcid":false,"given":"Debapriyo","family":"Sarmadhikari","sequence":"additional","affiliation":[{"name":"Computational Biophysics and CADD Group, Computational and Mathematical Biology Center, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad 121001, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vijay Kumar","family":"Singh","sequence":"additional","affiliation":[{"name":"Centre for Biological Sciences (Bioinformatics), Central University of South Bihar, Gaya Panchanpur Road, Bihar 824236, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3009-4226","authenticated-orcid":false,"given":"Antonella","family":"Fais","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, University of Cagliari, Monserrato, 09042 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2547-0071","authenticated-orcid":false,"given":"Amit","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Electrical and Electronic Engineering, University of Cagliari, Via Marengo 2, 09123 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shailendra","family":"Asthana","sequence":"additional","affiliation":[{"name":"Computational Biophysics and CADD Group, Computational and Mathematical Biology Center, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad 121001, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7981","DOI":"10.1073\/pnas.140220397","article-title":"Mechanism of action of a pestivirus antiviral compound","volume":"97","author":"Baginski","year":"2000","journal-title":"Proc. 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