Multiscale Simulation of Receptor–Drug Association Kinetics: Application to Neuraminidase Inhibitors

Journal of Chemical Theory and Computation

5 years ago

Multiscale Simulation of Receptor–Drug Association Kinetics: Application to Neuraminidase Inhibitors

Martin Zacharias, Rainer Bomblies, Manuel P. Luitz, Fabian Zeller

A detailed understanding of the drug–receptor association process is of fundamental importance for drug design. Due to the long time scales of typical binding kinetics, the atomistic simulation of the ligand traveling from bulk solution into the binding site is still computationally challenging. In this work, we apply a multiscale approach of combined Molecular Dynamics (MD) and Brownian Dynamics (BD) simulations to investigate association pathway ensembles for the two prominent H1N1 neuraminidase inhibitors oseltamivir and zanamivir. Including knowledge of the approximate binding site location allows for the selective confinement of detailed but expensive MD simulations and application of less demanding BD simulations for the diffusion controlled part of the association pathway. We evaluate a binding criterion based on the residence time of the inhibitor in the binding pocket and compare it to geometric criteria that require prior knowledge about the binding mechanism. The method ranks the association rates of both inhibitors in qualitative agreement with experiment and yields reasonable absolute values depending, however, on the reaction criteria. The simulated association pathway ensembles reveal that, first, ligands are oriented in the electrostatic field of the receptor. Subsequently, a salt bridge is formed between the inhibitor’s carboxyl group and neuraminidase residue Arg368, followed by adopting the native binding mode. Unexpectedly, despite oseltamivir’s higher overall association rate, the rate into the intermediate salt-bridge state was found to be higher for zanamivir. The present methodology is intrinsically parallelizable and, although computationally demanding, allows systematic binding rate calculation on selected sets of potential drug molecules.

Publisher URL: http://dx.doi.org/10.1021/acs.jctc.7b00631

DOI: 10.1021/acs.jctc.7b00631