Discovery of a novel binding trench in HIV integrase.
Docking of the 5CITEP inhibitor to snapshots of a 2 ns HIV-1 integrase MD trajectory indicated a previously uncharacterized trench adjacent to the active site that intermittently opens. Further docking studies of novel ligands with the potential to bind to both regions showed greater selective affinity when able to bind to the trench. Our ranking of ligands is open to experimental testing, and our approach suggests a new target for HIV-1 therapeutics.
Schames
Julie R
JR
Department of Pharmacology, Howard Hughes Medical Institute, University of California-San Diego, La Jolla, CA 92093-0365, USA.
Henchman
Richard H
RH
Siegel
Jay S
JS
Sotriffer
Christoph A
CA
Ni
Haihong
H
McCammon
J Andrew
JA
D001665:Binding Sites; D018360:Crystallography, X-Ray; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D007211:Indoles / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry
C400757:1-(5-chloroindol-3-yl)-3-hydroxy-3-(2H-tetrazol-5-yl)propenone; D007211:Indoles; D008024:Ligands; D009281:Naphthalenes; D013777:Tetrazoles; D019427:HIV Integrase