Qualitative Prediction of Ligand Dissociation Kinetics from Focal Adhesion Kinase Using Steered Molecular Dynamics.

Justin Spiriti,Chung F Wong

doi:10.3390/life11020074

Abstract

Most early-stage drug discovery projects focus on equilibrium binding affinity to the target alongside selectivity and other pharmaceutical properties. Since many approved drugs have nonequilibrium binding characteristics, there has been increasing interest in optimizing binding kinetics early in the drug discovery process. As focal adhesion kinase (FAK) is an important drug target, we examine whether steered molecular dynamics (SMD) can be useful for identifying drug candidates with the desired drug-binding kinetics. In simulating the dissociation of 14 ligands from FAK, we find an empirical power–law relationship between the simulated time needed for ligand unbinding and the experimental rate constant for dissociation, with a strong correlation depending on the SMD force used. To improve predictions, we further develop regression models connecting experimental dissociation rate with various structural and energetic quantities derived from the simulations. These models can be used to predict dissociation rates from FAK for related compounds.

Highlights

Most drugs function by binding to a specific target and altering its activity in a way that prevents or treats a disease
We first examined the free energy surface for the dissociation of ligands 32, 2, and 41 from the active site of focal adhesion kinase (FAK) to get a sense for the mechanism of dissociation and the location and nature of the activation barrier
Since only conformations in which the ligand was near the exit pathway previously identified by steered molecular dynamics (SMD) were sampled, only the free energy near this pathway was well estimated

Summary

Introduction

Most drugs function by binding to a specific target and altering its activity in a way that prevents or treats a disease. The most rigorous and computationally expensive methods involve alchemical free energy methods [2,3,4,5,6] These methods take advantage of the fact that free energy is a state function by effectively causing the ligand to appear within the binding site of the protein or in solvent and determining the free energy changes for these “alchemical” transformations. Other less rigorous methods include MM/PBSA and MM/GBSA methods [7,8], which determine the affinity using energies calculated from simulations with and without the ligand, and molecular docking, which uses scoring functions that have been fitted to correlate with the binding affinity [9,10,11]

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Discussion

Conclusion