Novel Method for the Evaluation of 3D Conformation Generators

Abstract

Conformation generation is a common and key process of computer-aided drug design. The reliability of the docking simulations, pharmacophore development, and 3D-QSAR analyses depends on the accuracy of conformations of small molecules used as input information for each program. Many conformation generators have been developed with the aim of efficiently generating all the putative bound conformations that small molecules adopt when they interact with macromolecules. Conformation generators have been evaluated by whether they can reproduce the experimentally determined bioactive conformations of bound small molecules. These bioactive conformations are usually obtained from publicly available crystal structures of protein-ligand complexes. However, it is difficult to obtain 2 or more than 2 bioactive conformations of one compound because multiple complex structures of a single molecule with various macromolecules are rarely available. Present methods, therefore, simply check whether a set of generated conformations includes the corresponding bioactive conformation. The overall validity of the entire set of generated conformations against bioactive conformation space has never been checked. In this work we developed a novel method for the evaluation of conformation generators, which makes it possible to measure the performance of a conformation generator based on its ability to reproduce the overall bioactive conformation space. We also determined the optimum parameter sets for OMEGA (OpenEye) based on the coverage of bioactive conformation space and computational efficiency. Our evaluation method elucidated that increasing the number of generated conformations is not necessary to obtain better reproducibility of the overall bioactive conformation space. Our method can be applied to the evaluation of the algorithm and/or design of the conformation generator program itself.