title: Optimization of azoles as anti-human immunodeficiency virus agents guided by free-energy calculations.
abstract: Efficient optimization of an inactive 2-anilinyl-5-benzyloxadiazole core has been guided by free energy perturbation (FEP) calculations to provide potent non-nucleoside inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (NNRTIs). An FEP "chlorine scan" was performed to identify the most promising sites for substitution of aryl hydrogens. This yielded NNRTIs 8 and 10 with activities (EC50) of 820 and 310 nM for protection of human T-cells from infection by wild-type HIV-1. FEP calculations for additional substituent modifications and change of the core heterocycle readily led to oxazoles 28 and 29, which were confirmed as highly potent anti-HIV agents with activities in the 10-20 nM range. The designed compounds were also monitored for possession of desirable pharmacological properties by use of additional computational tools. Overall, the trends predicted by the FEP calculations were well borne out by the assay results. FEP-guided lead optimization is confirmed as a valuable tool for molecular design including drug discovery; chlorine scans are particularly attractive since they are both straightforward to perform and highly informative.
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, USA.
authors.forename: Jacob G
authors.initials: JG
authors.lastname: Zeevaart
authors.forename: Ligong
authors.initials: L
authors.lastname: Wang
authors.forename: Vinay V
authors.initials: VV
authors.lastname: Thakur
authors.forename: Cheryl S
authors.initials: CS
authors.lastname: Leung
authors.forename: Julian
authors.initials: J
authors.lastname: Tirado-Rives
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bailey
authors.forename: Robert A
authors.initials: RA
authors.lastname: Domaoal
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
mesh_terms: D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D008958:Models, Molecular; D009010:Monte Carlo Method; D009154:Mutation; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D001393:Azoles; D010069:Oxadiazoles; D010080:Oxazoles; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase