SimG: An alignment based method for evaluating the similarity of small molecules and binding sites

In this study, a Gaussian volume overlap and chemical feature based molecular similarity metric was devised, and a downhill simplex searching was carried out to evaluate the corresponding similarity. By representing the shapes of both the candidate small molecules and the binding site with chemical features and comparing the corresponding Gaussian volumes overlaps, the active compounds could be identified. These two aspects compose the proposed method named SimG which supports both structure-based and ligand-based strategies. The validity of the proposed method was examined by analyzing the similarity score variation between actives and decoys as well as correlation among distinct reference methods. A retrospective virtual screening test was carried out on DUD data sets, demonstrating that the performance of structure-based shape matching virtual screening in DUD data sets is substantially dependent on some physical properties, especially the solvent-exposure extent of the binding site: The enrichments of targets with less solvent-exposed binding sites generally exceeds that of the one with more solvent-exposed binding sites and even surpasses the corresponding ligand-based virtual screening.