Fragment-based flexible ligand docking by evolutionary optimization

TitleFragment-based flexible ligand docking by evolutionary optimization
Publication TypeJournal Article
Year of Publication2001
AuthorsBudin N., Majeux N., Caflisch A.
JournalBiological Chemistry
Volume382
Issue9
Pagination1365-1372
Date Published2001 Sep
Type of ArticleResearch Article
ISSN1431-6730
KeywordsAlgorithms, Evolution, Molecular, HIV Protease, Hydrogen Bonding, Ligands, Models, Molecular, Protein Conformation, Thrombin
Abstract

A new computational approach for the efficient docking of flexible ligands in a rigid protein is presented. It exploits the binding modes of functional groups determined by an exhaustive search with solvation. The search in ligand conformational space is performed by a genetic algorithm whose scoring function approximates steric effects and intermolecular hydrogen bonds. Ligand conformations generated by the genetic algorithm are docked in the protein binding site by optimizing the fit of their fragments to optimal positions of chemically related functional groups. We show that the use of optimal binding modes of molecular fragments allows to dock known inhibitors with about ten rotatable bonds in the active site of the uncomplexed and complexed conformations of thrombin and HIV-1 protease.

DOI10.1515/BC.2001.168
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Alternate JournalBiol. Chem.
PubMed ID11688719
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