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488170 
Journal Article 
Prediction of binding modes for ligands in the cytochromes p450 and other heme-containing proteins 
Kirton, SB; Murray, CW; Verdonk, ML; Taylor, RD 
2005 
1 
Proteins: Structure, Function, and Genetics
ISSN: 0887-3585
EISSN: 1097-0134 
58 
4 
836-844 
English 
15651036 
The cytochromes P450 (P450s) are a family of heme-containing monooxygenase enzymes involved in a variety of functions, including the metabolism of endogenous and exogenous substances in the human body. During lead optimization, and in drug development, many potential drug candidates are rejected because of the affinity they display for drug-metabolising P450s. Recently, crystal structures of human enzymes involved in drug metabolism have been determined, significantly augmenting the prospect of using structure-based design to modulate the binding and metabolizing properties of compounds against P450 proteins. An important step in the application of structure-based metabolic optimization is the accurate prediction of docking modes in heme binding proteins. In this paper we assess the performance of the docking program GOLD at predicting the binding mode of 45 heme-containing complexes. We achieved success rates of 64% and 57% for Chemscore and Goldscore respectively; these success rates are significantly lower than the value of 79% observed with both scoring functions for the full GOLD validation set. Re-parameterization of metal-acceptor interactions and lipophilicity of planar nitrogen atoms in the scoring functions resulted in a significant increase in the percentage of successful dockings against the heme binding proteins (Chemscore 73%, Goldscore 65%). The modified scoring functions will be useful in docking applications on P450 enzymes and other heme binding proteins. (C) 2005 Wiley-Liss, Inc. 
docking; scoring functions; cytochrome P450; heme proteins; nitric-oxide synthase; arthromyces-ramosus peroxidase; cambridge; structural database; crystal-structure; angstrom resolution; genetic; algorithm; flexible docking; crystallographic analysis; cyp2c19; polymorphism; automated docking