Analysis of HIV wild-type and mutant structures via in silico docking against diverse ligand libraries.
|Title||Analysis of HIV wild-type and mutant structures via in silico docking against diverse ligand libraries.|
|Publication Type||Journal Article|
|Year of Publication||2007|
|Authors||Chang MW, Lindstrom W, Olson AJ, Belew RK|
|Journal||J Chem Inf Model|
|Date Published||2007 May-Jun|
|Keywords||Computer Simulation, HIV Protease, HIV Protease Inhibitors, HIV-1, Ligands, Mutation, Principal Component Analysis, Protein Binding, Structure-Activity Relationship|
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.
|Alternate Journal||J Chem Inf Model|