Effects of Water Placement on Predictions of Binding Affinities for p38α MAP Kinase Inhibitors

Abstract

Monte Carlo free energy perturbation (MC/FEP) calculations have been applied to compute the relative binding affinities of 17 congeneric pyridazo-pyrimidinone inhibitors of the protein p38α MAP kinase. Overall correlation with experiment was found to be modest when the complexes were hydrated using a traditional procedure with a stored solvent box. Significant improvements in accuracy were obtained when the MC/FEP calculations were repeated using initial solvent distributions optimized by the water placement algorithm JAWS. The results underscore the importance of accurate placement of water molecules in a ligand binding site for the reliable prediction of relative free energies of binding.

Strategies to Calculate Water Binding Free Energies in Protein–Ligand Complexes

“…JAWS has already been employed in free energy studies, whereby changes in hydration as a function of ligand perturbations evaluated. 46,47 With the extension of the JAWS biasing potential, both JAWS and GCMC can calculate the binding free energy for both strongly and weakly bound waters during a single simulation and take similar simulation times. However, one possible advantage in the JAWS approach is that once the optimal biasing potential is found no further simulations need to be run whilst the Based upon the excellent agreement between JAWS, GCMC and double-decoupling, it seems that ignoring the intermediate states is acceptable.…”

“…46 for structure-based molecular modelling. 47 Although the method is not capable of predicting the location of water molecules, the doubledecoupling method 48 is seen as the 'gold standard' in calculating the binding free energy of water molecules in protein-ligand complexes, owing to its rigorous methodology. The method involves running two simulations, whereby a water molecule is first decoupled from a box of bulk water, with a second simulation decoupling the water molecule from the protein-ligand complex.…”

Perspective: Alchemical free energy calculations for drug discovery

“…The Jorgensen lab at Yale routinely applies MC-based alchemical free energy calculations to help guide optimization of lead candidates in an early-stage drug discovery setting. 15,64 Several other groups in academia have applied them in similar efforts. [65][66][67] Industry has also found some use for these techniques, [68][69][70] and several studies have FIG.…”

Elucidation of Nonadditive Effects in Protein–Ligand Binding Energies: Thrombin as a Case Study

“…This was done here using an error analysis procedure described below. 47,48 The experimental and the predicted relative binding free energies related to the ligand Iterating the procedure n times yields probability distributions 2 , and of these metrics.…”