Pareto Optimization to Accelerate Multi-Objective Virtual Screening
Jenna C. Fromer David E. Graff Connor W. Coley
The discovery of therapeutic molecules is fundamentally a multi-objective
optimization problem. One formulation of the problem is to identify molecules
that simultaneously exhibit strong binding affinity for a target protein,
minimal off-target interactions, and suitable pharmacokinetic properties.
Inspired by prior work that uses active learning to accelerate the
identification of strong binders, we implement multi-objective Bayesian
optimization to reduce the computational cost of multi-property virtual
screening and apply it to the identification of ligands predicted to be
selective based on docking scores to on- and off-targets. We demonstrate the
superiority of Pareto optimization over scalarization across three case
studies. Further, we use the developed optimization tool to search a virtual
library of over 4M molecules for those predicted to be selective dual
inhibitors of EGFR and IGF1R, acquiring 100% of the molecules that form the
library's Pareto front after exploring only 8% of the library. This workflow
and associated open source software can reduce the screening burden of
molecular design projects and is complementary to research aiming to improve
the accuracy of binding predictions and other molecular properties.