Multisite λ Dynamics for Simulated Structure-Activity Relationship Studies

摘要

Multisite λ dynamics (MSλD) is a new free energy simulation method that is based on X dynamics. It has been developed to enable multiple substituents at multiple sites on a common ligand core to be modeled simultaneously and their free energies assessed. The efficacy of MSλD for estimating relative hydration free energies and relative binding affrnties is demonstrated using three test systems. Model compounds representing multiple identical benzene, dihydroxybenzene, and dimethoxybenzene molecules show that total combined MSλD trajectory lengths of ～1.5 ns are sufficient to reliably achieve relative hydration free energy estimates within 0.2 kcal/mol and are less sensitive to the number of trajectories that are used to generate these estimates for hybrid ligands that contain up to 10 substituents modeled at a single site or five substituents modeled at each of two sites. Relative hydration free energies among six benzene derivatives calculated from MSλD simulations are in very good agreement with those from alchemical free energy simulations (with average unsigned differences of 0.23 kcal/mol and R~2= 0.991) and the experiment (with average unsigned errors of 1.8 kcal/mol and R~2= 0.959). Estimates of the relative binding affinities among 14 inhibitors of HIV-1 reverse transcriptase obtained from MSλD simulations are in reasonable agreement with those from traditional free energy simulations and the experiment (average unsigned errors of 0.9 kcal/mol and R~2 = 0.402). For the same level of accuracy and precision, MSλD simulations are achieved ~20-50 times faster than traditional free energy simulations and thus with reliable force field parameters can be used effectively to screen tens to hundreds of compounds in structure-based drug design applications.