title: Enantioselective binding of second generation pyrrolobenzoxazepinones to the catalytic ternary complex of HIV-1 RT wild-type and L100I and K103N drug resistant mutants.
abstract: We investigated some pyrrolobenzoxazepinone (PBOs, 3e-i) analogues of early described effective non-nucleoside inhibitors of HIV-1 reverse transcriptase (RT). Enzymological studies of 3e-i enantiomers, with wild type (wt) RT and some drug-resistant mutants, revealed a stereoselective mode of action and selectivity for RT ternary complex. Unexpectedly (+)-3g was found more potent towards the L100I mutant than towards the wt RT, whereas (+)-3h inhibited the K103N mutant and RT wt with comparable potency.
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), via Aldo Moro, 2-Università di Siena, 53100 Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Borrelli
authors.forename: Isabella
authors.initials: I
authors.lastname: Fiorini
authors.forename: Alberta
authors.initials: A
authors.lastname: Samuele
authors.forename: Aristotele
authors.initials: A
authors.lastname: Karytinos
authors.forename: Marcella
authors.initials: M
authors.lastname: Facchini
authors.forename: Andrea
authors.initials: A
authors.lastname: Lossani
authors.forename: Samantha
authors.initials: S
authors.lastname: Zanoli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Federico
authors.initials: F
authors.lastname: Focher
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000187:drug effects; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009154:Mutation; D010077:Oxazepines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D010077:Oxazepines; D011758:Pyrroles; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase