Drug Discovery by Automated Adaptation of Chemical Structure and Identity.

Computer-aided drug design offers the potential to dramatically reduce the cost and effort required for drug discovery. While screening-based methods are valuable in the early stages of hit identification, they are frequently succeeded by iterative, hypothesis-driven computations that require recurrent investment of human time and intuition. To increase automation, we introduce a computational method for lead refinement that combines concerted dynamics of the ligand/protein complex via molecular dynamics simulations with integrated Monte Carlo-based changes in the chemical formula of the ligand. This approach, which we refer to as ligand-exchange Monte Carlo molecular dynamics, accounts for solvent- and entropy-based contributions to competitive binding free energies by coupling the energetics of bound and unbound states during the ligand-exchange attempt. Quantitative comparison of relative binding free energies to reference values from free energy perturbation, conducted in vacuum, indicates that ligand-exchange Monte Carlo molecular dynamics simulations sample relevant conformational ensembles and are capable of identifying strongly binding compounds. Additional simulations demonstrate the use of an implicit solvent model. We speculate that the use of chemical graphs in which exchanges are only permitted between ligands with sufficient similarity may enable an automated search to capture some of the benefits provided by human intuition during hypothesis-guided lead refinement.