{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:27:23Z","timestamp":1792009643792,"version":"4.4.0"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T00:00:00Z","timestamp":1648425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Drug-resistance-associated mutation in essential proteins of the viral life cycle is a major concern in anti-retroviral therapy. M46I, a non-active site mutation in HIV-1 protease has been clinically associated with saquinavir resistance in HIV patients. A 100 ns molecular dynamics (MD) simulation and MM-PBSA calculations were performed to study the molecular mechanism of M46I-mutation-based saquinavir resistance. In order to acquire deeper insight into the drug-resistance mechanism, the flap curling, closed\/semi-open\/open conformations, and active site compactness were studied. The M46I mutation significantly affects the energetics and conformational stability of HIV-1 protease in terms of RMSD, RMSF, Rg, SASA, and hydrogen formation potential. This mutation significantly decreased van der Waals interaction and binding free energy (\u2206G) in the M46I\u2013saquinavir complex and induced inward flap curling and a wider opening of the flaps for most of the MD simulation period. The predominant open conformation was reduced, but inward flap curling\/active site compactness was increased in the presence of saquinavir in M46I HIV-1 protease. In conclusion, the M46I mutation induced structural dynamics changes that weaken the protease grip on saquinavir without distorting the active site of the protein. The produced information may be utilized for the discovery of inhibitor(s) against drug-resistant HIV-1 protease.<\/jats:p>","DOI":"10.3390\/v14040697","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T21:45:51Z","timestamp":1648590351000},"page":"697","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation"],"prefix":"10.3390","volume":"14","author":[{"given":"Nilottam","family":"Rana","sequence":"first","affiliation":[{"name":"Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Bathinda 151401, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0081-6109","authenticated-orcid":false,"given":"Atul Kumar","family":"Singh","sequence":"additional","affiliation":[{"name":"Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Bathinda 151401, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohd","family":"Shuaib","sequence":"additional","affiliation":[{"name":"Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Bathinda 151401, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9492-3249","authenticated-orcid":false,"given":"Sanjay","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Urology, Pharmacology and Pathology, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4155-3379","authenticated-orcid":false,"given":"Mahmoud M.","family":"Habiballah","sequence":"additional","affiliation":[{"name":"Medical Laboratory Technology Department, Jazan University, Jazan 45142, Saudi Arabia"},{"name":"SMIRES for Consultation in Specialized Medical Laboratories, Jazan University, Jazan 45142, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustfa F.","family":"Alkhanani","sequence":"additional","affiliation":[{"name":"Emergency Service Department, College of Applied Sciences, AlMaarefa University, Riyadh 11597, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2989-121X","authenticated-orcid":false,"given":"Shafiul","family":"Haque","sequence":"additional","affiliation":[{"name":"Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan 45142, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0821-3660","authenticated-orcid":false,"given":"Mohd Salim","family":"Reshi","sequence":"additional","affiliation":[{"name":"Toxicology and Pharmacology Lab., Department of Zoology, School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University, Rajouri 185234, Jammu & Kashmir, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9622-0512","authenticated-orcid":false,"given":"Shashank","family":"Kumar","sequence":"additional","affiliation":[{"name":"Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Bathinda 151401, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s12977-020-00520-6","article-title":"Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors","volume":"17","author":"Bastys","year":"2020","journal-title":"Retrovirology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/0014-5793(84)81085-6","article-title":"The active site of aspartic proteinases","volume":"174","author":"Pearl","year":"1984","journal-title":"FEBS Lett."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Weber, I.T., Wang, Y.F., and Harrison, R.W. 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