{"doi":"10.3390/molecules28073103","title":"Targeting HIV-1 Reverse Transcriptase Using a Fragment-Based Approach","abstract":"Human immunodeficiency virus type I (HIV-1) is a retrovirus that infects cells of the host’s 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—a minimal but efficient NNRTI—offering a starting site for the development of novel dual NNIBP-Adjacent site inhibitors.","journal":"Molecules","year":2023,"id":363761,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1058408,"name":"Shawn Rumrill","orcid":"0000-0002-9590-3960","position":1,"is_corresponding":false},{"id":1118185,"name":"Shane Dawson","orcid":"0000-0003-2435-2193","position":2,"is_corresponding":false},{"id":347530,"name":"Adam Johnson","orcid":"0000-0002-2071-1526","position":3,"is_corresponding":false},{"id":845553,"name":"Jo‐Anne Pinson","orcid":"0000-0001-6654-0278","position":4,"is_corresponding":false},{"id":1118186,"name":"Menachem J. Gunzburg","orcid":"0000-0001-7314-4636","position":5,"is_corresponding":false},{"id":1118586,"name":"Catherine F. Latham","orcid":null,"position":6,"is_corresponding":false},{"id":872305,"name":"Νicholas Barlow","orcid":"0000-0002-5749-3542","position":7,"is_corresponding":false},{"id":1118187,"name":"George W. Mbogo","orcid":"0000-0002-2196-0495","position":8,"is_corresponding":false},{"id":521059,"name":"Paula Ellenberg","orcid":"0000-0002-7622-9106","position":9,"is_corresponding":false},{"id":647814,"name":"Stephen J. Headey","orcid":"0000-0001-8015-7064","position":10,"is_corresponding":false},{"id":294263,"name":"Nicolas Sluis‐Cremer","orcid":"0000-0003-3897-7450","position":11,"is_corresponding":false},{"id":848912,"name":"David Tyssen","orcid":null,"position":12,"is_corresponding":false},{"id":375979,"name":"Joseph D. Bauman","orcid":"0000-0002-4373-7673","position":13,"is_corresponding":false},{"id":296185,"name":"Francesc X. Ruiz","orcid":"0000-0002-0457-0030","position":14,"is_corresponding":false},{"id":296186,"name":"Eddy Arnold","orcid":"0000-0003-2612-9622","position":15,"is_corresponding":false},{"id":1118188,"name":"David K. Chalmers","orcid":"0000-0003-2366-569X","position":16,"is_corresponding":false},{"id":347541,"name":"Gilda Tachedjian","orcid":"0000-0002-7733-7037","position":17,"is_corresponding":false},{"id":1118184,"name":"Mahta Mansouri","orcid":"0000-0001-8428-5370","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T01:14:32.510714Z","pmid":"37049868","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}