Optimization and Evaluation of the Site-Identification by Ligand Competitive Saturation (SILCS) as a Tool for Target-Based Ligand Optimization

Chemical fragment cosolvent sampling techniques have become a versatile tool in ligand-protein binding prediction. Site-identification by ligand competitive saturation (SILCS) is one such method that maps the distribution of chemical fragments on a protein as free energy fields called FragMaps. Ligands are then simulated via Monte Carlo techniques in the field of the FragMaps (SILCS-MC) to predict their binding conformations and relative affinities for the target protein. Application of SILCS-MC using a number of different scoring schemes and MC sampling protocols against multiple protein targets was undertaken to evaluate and optimize the predictive capability of the method. Seven protein targets and 551 ligands with broad chemical variability were used to evaluate and optimize the model to maximize Pearson’s correlation coefficient, Pearlman’s predictive index, correct relative binding affinity, and root-mean-square error versus the absolute experimental binding affinities. Across the protein–ligand set...