{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:02:07Z","timestamp":1760148127155,"version":"build-2065373602"},"reference-count":53,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Medical Research Council (NHMRC) of Australia","doi-asserted-by":"publisher","award":["GNT1064900","GNT1119940","R01 AI027690","T32 GM008339","T32 GM135141","GNT1117748"],"award-info":[{"award-number":["GNT1064900","GNT1119940","R01 AI027690","T32 GM008339","T32 GM135141","GNT1117748"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institutes of Health (NIH)","award":["GNT1064900","GNT1119940","R01 AI027690","T32 GM008339","T32 GM135141","GNT1117748"],"award-info":[{"award-number":["GNT1064900","GNT1119940","R01 AI027690","T32 GM008339","T32 GM135141","GNT1117748"]}]},{"name":"National Institute of General Medical Sciences of the National Institutes of Health Training","award":["GNT1064900","GNT1119940","R01 AI027690","T32 GM008339","T32 GM135141","GNT1117748"],"award-info":[{"award-number":["GNT1064900","GNT1119940","R01 AI027690","T32 GM008339","T32 GM135141","GNT1117748"]}]},{"DOI":"10.13039\/501100000925","name":"NHMRC Senior Research Fellowship","doi-asserted-by":"publisher","award":["GNT1064900","GNT1119940","R01 AI027690","T32 GM008339","T32 GM135141","GNT1117748"],"award-info":[{"award-number":["GNT1064900","GNT1119940","R01 AI027690","T32 GM008339","T32 GM135141","GNT1117748"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Human immunodeficiency virus type I (HIV-1) is a retrovirus that infects cells of the host\u2019s immune system leading to acquired immunodeficiency syndrome and potentially death. Although treatments are available to prevent its progression, HIV-1 remains a major burden on health resources worldwide. Continued emergence of drug-resistance mutations drives the need for novel drugs that can inhibit HIV-1 replication through new pathways. The viral protein reverse transcriptase (RT) plays a fundamental role in the HIV-1 replication cycle, and multiple approved medications target this enzyme. In this study, fragment-based drug discovery was used to optimize a previously identified hit fragment (compound B-1), which bound RT at a novel site. Three series of compounds were synthesized and evaluated for their HIV-1 RT binding and inhibition. These series were designed to investigate different vectors around the initial hit in an attempt to improve inhibitory activity against RT. Our results show that the 4-position of the core scaffold is important for binding of the fragment to RT, and a lead compound with a cyclopropyl substitution was selected and further investigated. Requirements for binding to the NNRTI-binding pocket (NNIBP) and a novel adjacent site were investigated, with lead compound 27\u2014a minimal but efficient NNRTI\u2014offering a starting site for the development of novel dual NNIBP-Adjacent site inhibitors.<\/jats:p>","DOI":"10.3390\/molecules28073103","type":"journal-article","created":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T02:08:01Z","timestamp":1680228481000},"page":"3103","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting HIV-1 Reverse Transcriptase Using a Fragment-Based Approach"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8428-5370","authenticated-orcid":false,"given":"Mahta","family":"Mansouri","sequence":"first","affiliation":[{"name":"Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9590-3960","authenticated-orcid":false,"given":"Shawn","family":"Rumrill","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shane","family":"Dawson","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Johnson","sequence":"additional","affiliation":[{"name":"Retroviral Biology and Antivirals Laboratory, Disease Elimination Program, Life Sciences Discipline, Burnet Institute, Melbourne, VIC 3004, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6654-0278","authenticated-orcid":false,"given":"Jo-Anne","family":"Pinson","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Menachem J.","family":"Gunzburg","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine F.","family":"Latham","sequence":"additional","affiliation":[{"name":"Retroviral Biology and Antivirals Laboratory, Disease Elimination Program, Life Sciences Discipline, Burnet Institute, Melbourne, VIC 3004, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Barlow","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George W.","family":"Mbogo","sequence":"additional","affiliation":[{"name":"Retroviral Biology and Antivirals Laboratory, Disease Elimination Program, Life Sciences Discipline, Burnet Institute, Melbourne, VIC 3004, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paula","family":"Ellenberg","sequence":"additional","affiliation":[{"name":"Retroviral Biology and Antivirals Laboratory, Disease Elimination Program, Life Sciences Discipline, Burnet Institute, Melbourne, VIC 3004, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8015-7064","authenticated-orcid":false,"given":"Stephen J.","family":"Headey","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Sluis-Cremer","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Tyssen","sequence":"additional","affiliation":[{"name":"Retroviral Biology and Antivirals Laboratory, Disease Elimination Program, Life Sciences Discipline, Burnet Institute, Melbourne, VIC 3004, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph D.","family":"Bauman","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0457-0030","authenticated-orcid":false,"given":"Francesc X.","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2612-9622","authenticated-orcid":false,"given":"Eddy","family":"Arnold","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2366-569X","authenticated-orcid":false,"given":"David K.","family":"Chalmers","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, 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