title: Virtual screening based identification of novel small-molecule inhibitors targeted to the HIV-1 capsid.
abstract: The hydrophobic cavity of the C-terminal domain (CTD) of HIV-1 capsid has been recently validated as potential target for antiviral drugs by peptide-based inhibitors; however, there is no report yet of any small molecule compounds that target this hydrophobic cavity. In order to fill this gap and discover new classes of ant-HIV-1 inhibitors, we undertook a docking-based virtual screening and subsequent analog search, and medicinal chemistry approaches to identify small molecule inhibitors against this target. This article reports for the first time, to the best of our knowledge, identification of diverse classes of inhibitors that efficiently inhibited the formation of mature-like viral particles verified under electron microscope (EM) and showed potential as anti-HIV-1 agents in a viral infectivity assay against a wide range of laboratory-adapted as well as primary isolates in MT-2 cells and PBMC. In addition, the virions produced after the HIV-1 infected cells were treated with two of the most active compounds showed drastically reduced infectivity confirming the potential of these compounds as anti-HIV-1 agents. We have derived a comprehensive SAR from the antiviral data. The SAR analyses will be useful in further optimizing the leads to potential anti-HIV-1 agents.
authors.affiliation: Laboratory of Molecular Modeling & Drug Design, Lindsley F. Kimball Research Institute of the New York Blood Center, 310 E 67th Street, New York, NY 10065, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Curreli
authors.forename: Hongtao
authors.initials: H
authors.lastname: Zhang
authors.forename: Xihui
authors.initials: X
authors.lastname: Zhang
authors.forename: Ilya
authors.initials: I
authors.lastname: Pyatkin
authors.forename: Zagorodnikov
authors.initials: Z
authors.lastname: Victor
authors.forename: Andrea
authors.initials: A
authors.lastname: Altieri
authors.forename: Asim K
authors.initials: AK
authors.lastname: Debnath
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002213:Capsid / Q000187:drug effects*; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008854:Microscopy, Electron; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents