ROCS-Derived Features for Virtual Screening

Ligand-based virtual screening is based on the assumption that similar compounds have similar biological activity [Willett, 2009]. Compound similarity can be assessed in many ways, including comparisons of molecular "fingerprints" that encode structural features or molecular properties [Todeschini and Consonni, 2009] and measurements of shape, chemical, and/or electrostatic similarity in three dimensions [Hawkins et al., 2007; Muchmore et al., 2006; Ballester and Richards, 2007]. Three-dimensional approaches such as rapid overlay of chemical structures (ROCS) [Hawkins et al., 2007] are especially interesting because of their potential to identify molecules that are similar from the point of view of a target protein but dissimilar in underlying chemical structure ("scaffold hopping"; [Böhm et al., 2004]). ROCS represents atoms as three-dimensional Gaussian functions [Grant and Pickup, 1995; Grant et al., 1996] and calculates similarity as a function of volume overlaps between alignments of pre-generated molecular conformers. Chemical ("color") similarity is measured by overlaps between dummy atoms marking interesting chemical functionalities: hydrogen bond donors and acceptors, charged functional groups, rings, and hydrophobic groups.