title: Development of indole compounds as small molecule fusion inhibitors targeting HIV-1 glycoprotein-41.
abstract: Nonpeptide inhibition of fusion remains an important goal in anti-HIV research, due to its potential for low cost prophylaxis or prevention of cell-cell transmission of the virus. We report here on a series of indole compounds that have been identified as fusion inhibitors of gp41 through a structure-based drug design approach. Experimental binding affinities of the compounds for the hydrophobic pocket were strongly correlated to fusion inhibitory data (R(2) = 0.91), and corresponding inhibition of viral replication confirmed the hydrophobic pocket as a valid target for low molecular weight fusion inhibitors. The most active compound bound to the hydrophobic pocket and inhibited cell-cell fusion and viral replication at submicromolar levels. A common binding mode for the inhibitors in this series was established by carrying out docking studies using structures of gp41 in the Protein Data Bank. The molecules were flexible enough to conform to the contours of the pocket, and the most active compound was able to adopt a structure mimicking the hydrophobic contacts of the D-peptide PIE7. The results enhance our understanding of indole compounds as inhibitors of gp41.
authors.affiliation: Department of Basic Sciences, Touro University-California, 1310 Club Drive, Mare Island, Vallejo, California 94592, United States. guangyan.zhou@tu.edu
authors.forename: Guangyan
authors.initials: G
authors.lastname: Zhou
authors.forename: Dong
authors.initials: D
authors.lastname: Wu
authors.forename: Beth
authors.initials: B
authors.lastname: Snyder
authors.forename: Roger G
authors.initials: RG
authors.lastname: Ptak
authors.forename: Harmeet
authors.initials: H
authors.lastname: Kaur
authors.forename: Miriam
authors.initials: M
authors.lastname: Gochin
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors*; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008561:Membrane Fusion / Q000187:drug effects; D008958:Models, Molecular; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D007211:Indoles