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The emergence of antiviral\u2010resistant strains of HIV\u20101 poses a substantial challenge in the treatment of HIV. This study presents an innovative virtual screening method that integrates a drug screening approach based on molecular structure to identify potential inhibitors for drug\u2010resistant HIV\u20101 strains. Wild\u2010type reverse transcriptase and a proposed multi\u2010mutant variant were identified as target proteins for structure\u2010based virtual screening. For better interpretation, selected compounds were used for molecular docking and molecular dynamics simulation. Six compounds with strong binding affinities were identified from the Comprehensive Marine Natural Products Database (CMNPD) as potential NNRTI candidates. In CMNPD database six compounds were identifed that have potential activity against the multi\u2010mutant reverse transcriptase enzyme of HIV\u20101. Molecular modeling studies revealed that the highest\u2010ranking compound (CMNPD370) binds persistently and with significant affinity to the multi\u2010mutant HIV\u2010RT. Molecular mechanics\/generalized born surface area analysis revealed CMNPD370 binds more strongly to the mutant reverse transcriptase (RT) compared to the wild\u2010type, as indicated by a more negative total binding free energy (\u0394G_bind) of \u201317697.64\u00a0kcal\/mol versus \u201315503.75\u00a0kcal\/mol. The results demonstrate that our proposed method is feasible, reliable, and effective. Our findings may facilitate the development of novel NNRTIs targeting drug\u2010resistant strains and offer new insights for identifying natural therapies for HIV.<\/jats:p>","DOI":"10.1002\/cpdd.1585","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T14:00:47Z","timestamp":1756303247000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Computer\u2010Aided Algorithmic Approaches to Drug Development for Multi\u2010Mutant HIV\u20101 Reverse Transcriptase"],"prefix":"10.1002","volume":"15","author":[{"given":"Akmal","family":"Zubair","sequence":"first","affiliation":[{"name":"Department of Biotechnology Quaid\u2010i\u2010Azam University  Islamabad Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Biotechnology Quaid\u2010i\u2010Azam University  Islamabad Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud M.","family":"Hessien","sequence":"additional","affiliation":[{"name":"Department of Chemistry College of Science Taif University  Taif Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10989-025-10702-5"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11262-025-02149-z"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clindermatol.2024.02.001"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s44197-023-00097-1"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1377403"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.13.6320"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0409823102"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0802203105"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7824947"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0317382"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/373123a0"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.22080"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/313277a0"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(85)90303-4"},{"key":"e_1_2_10_16_1","unstructured":"SpivakA AndradeA HohR BacchettiP EiseleE BuckheitIIIR eds.Safety and feasibility of using disulfiram to enhance HIV transcription among long\u2010term ARV\u2010treated adults: preliminary results from a pilot study. 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