Application of Site-Identification by Ligand Competitive Saturation in Computer-Aided Drug Design

New J Chem. 2022 Jan 21;46(3):919-932. doi: 10.1039/d1nj04028f. Epub 2021 Nov 29.


Site Identification by Ligand Competitive Saturation (SILCS) is a molecular simulation approach that uses diverse small solutes in aqueous solution to obtain functional group affinity patterns of a protein or other macromolecule. This involves employing a combined Grand Canonical Monte Carlo (GCMC)-molecular dynamics (MD) method to sample the full 3D space of the protein, including deep binding pockets and interior cavities from which functional group free energy maps (FragMaps) are obtained. The information content in the maps, which include contributions from protein flexibilty and both protein and functional group desolvation contributions, can be used in many aspects of the drug discovery process. These include identification of novel ligand binding pockets, including allosteric sites, pharmacophore modeling, prediction of relative protein-ligand binding affinities for database screening and lead optimization efforts, evaluation of protein-protein interactions as well as in the formulation of biologics-based drugs including monoclonal antibodies. The present article summarizes the various tools developed in the context of the SILCS methodology and their utility in computer-aided drug design (CADD) applications, showing how the SILCS toolset can improve the drug-development process on a number of fronts with respect to both accuracy and throughput representing a new avenue of CADD applications.