Development of Indole Compounds as Small Molecule Fusion Inhibitors Targeting HIV-1 Glycoprotein-41
- 3 October 2011
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 54 (20), 7220-7231
- https://doi.org/10.1021/jm200791z
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.Keywords
This publication has 41 references indexed in Scilit:
- Paramagnetic Relaxation Assisted Docking of a Small Indole Compound in the HIV-1 gp41 Hydrophobic PocketACS Chemical Biology, 2010
- Design, synthesis, and evaluation of indole compounds as novel inhibitors targeting Gp41Bioorganic & Medicinal Chemistry Letters, 2010
- Structure-based design, synthesis and biological evaluation of new N-carboxyphenylpyrrole derivatives as HIV fusion inhibitors targeting gp41Bioorganic & Medicinal Chemistry Letters, 2010
- Design, Synthesis, and Structure−Activity Relationship of a Novel Series of 2-Aryl 5-(4-Oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans as HIV-1 Entry InhibitorsJournal of Medicinal Chemistry, 2009
- NMR Second Site Screening for Structure Determination of Ligands Bound in the Hydrophobic Pocket of HIV-1 gp41Journal of the American Chemical Society, 2009
- Design, Synthesis, and Biological Evaluation of N-Carboxyphenylpyrrole Derivatives as Potent HIV Fusion Inhibitors Targeting gp41Journal of Medicinal Chemistry, 2008
- Reaching for high-hanging fruit in drug discovery at protein–protein interfacesNature, 2007
- Potent D-peptide inhibitors of HIV-1 entryProceedings of the National Academy of Sciences of the United States of America, 2007
- Small molecules that bind the inner core of gp41 and inhibit HIV envelope-mediated fusionProceedings of the National Academy of Sciences of the United States of America, 2006
- Evaluation of “Credit Card” Libraries for Inhibition of HIV-1 gp41 Fusogenic Core FormationJournal of Combinatorial Chemistry, 2006