Analysis of HIV wild-type and mutant structures via in silico docking against diverse ligand libraries.
The FightAIDS@Home distributed computing project uses AutoDock for an initial virtual screen of HIV protease structures against a broad range of 1771 ligands including both known protease inhibitors and a diverse library of other ligands. The volume of results allows novel large-scale analyses of binding energy "profiles" for HIV structures. Beyond identifying potential lead compounds, these characterizations provide methods for choosing representative wild-type and mutant protein structures from the larger set. From the binding energy profiles of the PDB structures, a principal component analysis based analysis identifies seven "spanning" proteases. A complementary analysis finds that the wild-type protease structure 2BPZ best captures the central tendency of the protease set. Using a comparison of known protease inhibitors against the diverse ligand set yields an AutoDock binding energy "significance" threshold of -7.0 kcal/mol between significant, strongly binding ligands and other weak/nonspecific binding energies. This threshold captures nearly 98% of known inhibitor interactions while rejecting more than 95% of suspected noninhibitor interactions. These methods should be of general use in virtual screening projects and will be used to improve further FightAIDS@Home experiments.
Chang
Max W
MW
Bioinformatics Program, University of California-San Diego, La Jolla, California 92093, USA. mchang@ucsd.edu
Lindstrom
William
W
Olson
Arthur J
AJ
Belew
Richard K
RK
D003198:Computer Simulation; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008024:Ligands; D009154:Mutation; D025341:Principal Component Analysis; D011485:Protein Binding; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D008024:Ligands; D016333:HIV Protease