title: From docking false-positive to active anti-HIV agent.
abstract: Virtual screening of the Maybridge library of ca. 70 000 compounds was performed using a similarity filter, docking, and molecular mechanics-generalized Born/surface area postprocessing to seek potential non-nucleoside inhibitors of human immunodeficiency virus-1 (HIV-1) reverse transcriptase (NNRTIs). Although known NNRTIs were retrieved well, purchase and assaying of representative, top-scoring compounds from the library failed to yield any active anti-HIV agents. However, the highest-ranked library compound, oxadiazole 1, was pursued as a potential "near-miss" with the BOMB program to seek constructive modifications. Subsequent synthesis and assaying of several polychloro-analogs did yield anti-HIV agents with EC50 values as low as 310 nM. The study demonstrates that it is possible to learn from a formally unsuccessful virtual-screening exercise and, with the aid of computational analyses, to efficiently evolve a false positive into a true active.
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Barreiro
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Kim
authors.forename: Cristiano R W
authors.initials: CR
authors.lastname: Guimarães
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bailey
authors.forename: Robert A
authors.initials: RA
authors.lastname: Domaoal
authors.forename: Ligong
authors.initials: L
authors.lastname: Wang
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; D002460:Cell Line; D016208:Databases, Factual; D054303:HIV Reverse Transcriptase / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D019380:Anti-HIV Agents; D008024:Ligands; D010069:Oxadiazoles; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase