Using Spherical Harmonic Surface Property Representations for Ligand-Based Virtual Screening

Ligand-based virtual screening (VS) techniques have become well established in the drug discovery process. However, despite their relative success, there still exists the problem of how to define the initial query compounds and which of their conformations should be used. Here, we propose a novel shape plus surface property approach using multiple local spherical harmonic (SH) functions. We also investigate the use of shape-based and shape plus property-based consensus SH queries calculated in several different ways. The utility of these approaches is compared using the 40 pharmaceutically relevant targets of the DUD database. Our results show that using a combination of SH-based properties often gives better VS performance than using simple shape-based queries. Shape-based consensus queries also perform well, but we find that explicit 3D shape-property conformations should be retained for highly flexible ligands.