Alpha sphere filter method: Application of pseudomolecular descriptors in virtual screening of 2D chemical structures

Alpha sphere filter (ASF) method is a novel previrtual screening method to undertake a rapid virtual screening of a huge chemical space. The small‐molecule binding site of a target molecule can be characterized by a set of alpha spheres generated at the site. Two types of pseudomolecules representing molecules that likely fit into the binding site were molded from the set of alpha spheres. Based on the pseudomolecules, pseudomolecular descriptors corresponding to the conventional two‐dimensional (2D) molecular descriptors were calculated. The correlations between the pseudomolecular descriptors and the 2D molecular descriptors were analyzed for a set of high‐quality X‐ray structures of the complexes between ligands and proteins. By use of these correlations, specific value ranges of the 2D molecular descriptors were determined. These value ranges were applied in virtual screening. In a trial to screen 200 active ligands out of a chemical database with 42,547 molecules, the enrichment rate of 5.8 was attained. The enrichment rate was good enough for a prescreening tool prior to docking simulations. As the ASF method screens molecules by 2D molecular descriptors, it is rapid enough to screen a huge chemical space and could significantly decrease the number of trivial compounds to be considered in the following docking simulations. Therefore, the ASF method can contribute to enlarge the possibility of virtual screening. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010