Leveraging Data Fusion Strategies in Multireceptor Lead Optimization MM/GBSA End-Point Methods.

Accurate and efficient affinity calculations are critical to enhancing the contribution of in silico modeling during the lead optimization phase of a drug discovery campaign. Here, we present a large-scale study of the efficacy of data fusion strategies to leverage results from end-point MM/GBSA calculations in multiple receptors to identify potent inhibitors among an ensemble of congeneric ligands. The retrospective analysis of 13 congeneric ligand series curated from publicly available data across seven biological targets demonstrates that in 90% of the individual receptor structures MM/GBSA scores successfully identify subsets of inhibitors that are more potent than a random selection, and data fusion strategies that combine MM/GBSA scores from each of the receptors significantly increase the robustness of the predictions. Among nine different data fusion metrics based on consensus scores or receptor rankings, the SumZScore (i.e., converting MM/GBSA scores into standardized Z-Scores within a receptor and computing the sum of the Z-Scores for a given ligand across the ensemble of receptors) is found to be a robust and physically meaningful metric for combining results across multiple receptors. Perhaps most surprisingly, even with relatively low to modest overall correlations between SumZScore and experimental binding affinities, SumZScore tends to reliably prioritize subsets of inhibitors that are at least as potent as those that are prioritized from a "best" single receptor identified from known compounds within the congeneric series.