title: Computationally-guided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents.
abstract: A 5-μM docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (FEP) calculations to predict relative free energies of binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most potent resultant catechol diethers feature terminal uracil and cyanovinylphenyl groups. A halogen bond with Pro95 likely contributes to the extreme potency of compound 42. In addition, several examples are provided illustrating failures of attempted grafting of a substructure from a very active compound onto a seemingly related scaffold to improve its activity.
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.
authors.forename: Mariela
authors.initials: M
authors.lastname: Bollini
authors.forename: Robert A
authors.initials: RA
authors.lastname: Domaoal
authors.forename: Vinay V
authors.initials: VV
authors.lastname: Thakur
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gallardo-Macias
authors.forename: Krasimir A
authors.initials: KA
authors.lastname: Spasov
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002396:Catechols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology
chemical_list: D019380:Anti-HIV Agents; D002396:Catechols; D004987:Ethers; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase
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