title: Small molecule inhibitors of HIVgp41 N-heptad repeat trimer formation.
abstract: Identification of mechanistically novel anti-HIV fusion inhibitors was accomplished using a computer-aided structure-based design approach with the goal of blocking the formation of the N-heptad repeat (NHR) trimer of the viral protein gp41. A virtual screening strategy that included per-residue interaction patterns (footprints) was employed to identify small molecules compatible with putative binding pockets at the internal interface of the NHR helices at the core native viral six-helix bundle. From a screen of ∼2.8 million compounds using the DOCK program, 120 with favorable energetic and footprint overlap characteristics were purchased and experimentally tested leading to two compounds with favorable cell-cell fusion (IC50) and cytotoxicity profiles. Importantly, both hits were identified on the basis of scores containing footprint overlap terms and would not have been identified using the standard DOCK energy function alone. To our knowledge, these compounds represent the first reported small molecules that inhibit viral entry via the proposed NHR-trimer obstruction mechanism.
authors.affiliation: Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, NY 11794, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Allen
authors.affiliation: Department of Microbiology and Immunology, State University of New York at Buffalo, Buffalo, NY 14214, United States.
authors.forename: Hyun Ah
authors.initials: HA
authors.lastname: Yi
authors.affiliation: Department of Basic Sciences, Touro University-California, Mare Island, Vallejo, CA 94592, United States; Department of Pharmaceutical Chemistry, University of California San Francisco, CA 94143, United States.
authors.forename: Miriam
authors.initials: M
authors.lastname: Gochin
authors.affiliation: Department of Microbiology and Immunology, State University of New York at Buffalo, Buffalo, NY 14214, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Jacobs
authors.affiliation: Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, NY 11794, United States; Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States; Laufer Center for Physical & Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, United States. Electronic address: rizzorc@gmail.com.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rizzo
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D055503:Protein Multimerization / Q000187:drug effects; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D054852:Small Molecule Libraries
keywords: DOCK; Docking; Footprint similarity; HIV; Virtual screening; gp41