Molecular dynamics free energy simulation study to rationalize the relative activities of PPARδ agonists

Abstract

As a computational method for the discovery of the effective agonists for PPARδ, we address the usefulness of molecular dynamics free energy (MDFE) simulation with explicit solvent in terms of the accuracy and the computing cost. For this purpose, we establish an efficient computational protocol of thermodynamic integration (TI) that is superior to free energy perturbation (FEP) method in parallel computing environment. Using this protocol, the relative binding affinities of GW501516 and its derivatives for PPARδ are calculated. The accuracy of our protocol was evaluated in two steps. First, we devise a thermodynamic cycle to calculate the absolute and relative hydration free energies of test molecules. This allows a self-consistent check for the accuracy of the calculation protocol. Second, the calculated relative binding affinities of the selected ligands are compared with experimental IC 50 values. The average deviation of the calculated binding free energies from the experimental results amounts at the most to 1 kcal/mol. The computational efficiency of current protocol is also assessed by comparing its execution times with those of the sequential version of the TI protocol. The results show that the calculation can be accelerated by 4 times when compared to the sequential run. Based on the calculations with the parallel computational protocol, a new potential agonist of GW501516 derivative is proposed.