Evaluating docking programs: keeping the playing field level

• Published in: Journal of computer-aided molecular design Vol. 22; no. 3-4; pp. 229 - 238
• Main Author: Liebeschuetz, John W.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.03.2008; Springer Nature B.V
• Subjects: Animal Anatomy; Binding sites; Binding Sites - physiology; Biotechnology; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Computer-Aided Design; Evaluation Studies as Topic; Experimental design; Histology; Models, Molecular; Molecular biology; Morphology; Pharmacology; Physical Chemistry; Protein Binding - physiology; Proteins; Structural models; Enrichment; Protein–ligand interaction; GOLD; Virtual screening; Docking; Factor Xa; Thrombin
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-008-9169-8

Over recent years many enrichment studies have been published which purport to rigorously compare the performance of two or more docking protocols. It has become clear however that such studies often have flaws within their methodologies, which cast doubt on the rigour of the conclusions. Setting up such comparisons is fraught with difficulties and no best mode of practice is available to guide the experimenter. Careful choice of structural models and ligands appropriate to those models is important. The protein structure should be representative for the target. In addition the set of active ligands selected should be appropriate to the structure in cases where different forms of the protein bind different classes of ligand. Binding site definition is also an area in which errors arise. Particular care is needed in deciding which crystallographic waters to retain and again this may be predicated by knowledge of the likely binding modes of the ligands making up the active ligand list. Geometric integrity of the ligand structures used is clearly important yet it is apparent that published sets of actives + decoys may contain sometimes high proportions of incorrect structures. Choice of protocol for docking and analysis needs careful consideration as many programs can be tweaked for optimum performance. Should studies be run using ‘black box’ protocols supplied by the software provider? Lastly, the correct method of analysis of enrichment studies is a much discussed topic at the moment. However currently promoted approaches do not consider a crucial aspect of a successful virtual screen, namely that a good structural diversity of hits be returned. Overall there is much to consider in the experimental design of enrichment studies. Hopefully this study will be of benefit in helping others plan such experiments.