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Keywords:

  • protein–ligand docking;
  • PDBbind database;
  • molecular recognition;
  • software evaluation;
  • scoring functions

Abstract

Docking is one of the most commonly used techniques in drug design. It is used for both identifying correct poses of a ligand in the binding site of a protein as well as for the estimation of the strength of protein–ligand interaction. Because millions of compounds must be screened, before a suitable target for biological testing can be identified, all calculations should be done in a reasonable time frame. Thus, all programs currently in use exploit empirically based algorithms, avoiding systematic search of the conformational space. Similarly, the scoring is done using simple equations, which makes it possible to speed up the entire process. Therefore, docking results have to be verified by subsequent in vitro studies. The purpose of our work was to evaluate seven popular docking programs (Surflex, LigandFit, Glide, GOLD, FlexX, eHiTS, and AutoDock) on the extensive dataset composed of 1300 protein–ligands complexes from PDBbind 2007 database, where experimentally measured binding affinity values were also available. We compared independently the ability of proper posing [according to Root mean square deviation (or Root mean square distance) of predicted conformations versus the corresponding native one] and scoring (by calculating the correlation between docking score and ligand binding strength). To our knowledge, it is the first large-scale docking evaluation that covers both aspects of docking programs, that is, predicting ligand conformation and calculating the strength of its binding. More than 1000 protein–ligand pairs cover a wide range of different protein families and inhibitor classes. Our results clearly showed that the ligand binding conformation could be identified in most cases by using the existing software, yet we still observed the lack of universal scoring function for all types of molecules and protein families. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011