Accurate Calculations of Ligand Binding Free Energies: Chiral Separation with Enantioselective Receptors

Abstract

Qualitatively accurate calculations of ligand binding free energies (BFEs) as applied to chiral selective receptors using the MINTA (mode integration) algorithm are presented. Extensive conformational searches are first performed using a mixed mode Monte Carlo algorithm (MCMM/LMCS) followed by computation of the BFEs using the MINTA approach. The Merck (MMFFs) force field is used throughout. Deficiencies in the default MMFFs partial charges and torsion parameters assigned to atoms directly involved in substrate binding are systematically removed by reparametrization of these parameters using the program PAROPT and on the basis of Jaguar quantum mechanics calculations. The new force field parameters lead to a systematic improvement in qualitative trends of BFE differences (ΔΔGL-D) for different receptors as compared with the experimental enantioselectivities (ee's). The results suggest that this method can be extended to a larger and more complex class of receptors such as proteins.