Abstract
Drug discovery is accelerated with computational methods such as alchemical simulations to estimate ligand affinities. In particular, relative binding free energy (RBFE) simulations are beneficial for lead optimization. To use RBFE simulations to compare prospective ligands in silico, researchers first plan the simulation experiment, using graphs where nodes represent ligands and graph edges represent alchemical transformations between ligands. Recent work demonstrated that optimizing the statistical architecture of these perturbation graphs improves the accuracy of the predicted changes in the free energy of ligand binding. Therefore, to improve the success rate of computational drug discovery, we present the open-source software package High Information Mapper (HiMap)─a new take on its predecessor, Lead Optimization Mapper (LOMAP). HiMap removes heuristics decisions from design selection and instead finds statistically optimal graphs over ligands clustered with machine learning. Beyond optimal design generation, we present theoretical insights for designing alchemical perturbation maps. Some of these results include that for n number of nodes, the precision of perturbation maps is stable at n·ln(n) edges. This result indicates that even an "optimal" graph can result in unexpectedly high errors if a plan includes too few alchemical transformations for the given number of ligands and edges. And, as a study compares more ligands, the performance of even optimal graphs will deteriorate with linear scaling of the edge count. In this sense, ensuring an A- or D-optimal topology is not enough to produce robust errors. We additionally find that optimal designs will converge more rapidly than radial and LOMAP designs. Moreover, we derive bounds for how clustering reduces cost for designs with a constant expected relative error per cluster, invariant of the size of the design. These results inform how to best design perturbation maps for computational drug discovery and have broader implications for experimental design.