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

Abstract

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.

Dynamic Docking: A Paradigm Shift in Computational Drug Discovery

“…Very recently, Zeller et al introduced a multiscale approach to dynamic docking that allows the binding kinetics to be evaluated. As a test case, they used two H1N1 neuroaminidase inhibitors, oseltamivir and zanamivir [ 104 ]. Their implementation used Brownian Dynamics (BD) [ 105 ] when the distance between the ligand and binding site was more than a properly defined value.…”

“…This is a crucial aspect of unbiased dynamic docking because it expands the predictive power of computational methods applied to SBDD. Notably, the estimation of kinetic constants is the focus of the most sophisticated approaches developed so far [ 90 , 97 , 98 , 104 , 107 ]. In particular, from a drug discovery standpoint, accurately predicting the k off can be as important as estimating the binding free energy.…”

Predicting Ligand Binding Kinetics Using a Markovian Milestoning with Voronoi Tessellations Multiscale Approach

“…Additionally, multiscale methods exist that integrate MD with other approaches such as quantum mechanics or BD, or continuum approaches to better predict kinetic parameters by improving either accuracy or scalability. [47][48][49][50][51][52][53] One such multiscale approach is the MD/BD/milestoning methodology "Simulation Enabled Estimation of Kinetic Rates" (SEEKR) which we develop and have shown to be effective for the calculation of both kon and koff as well as the rank ordering of compounds by their rates. [54][55][56] Milestoning theory facilitates the division of simulation space into smaller regions called milestones that can be simulated independently and in parallel.57-60 SEEKR uses atomistic, fully flexible MD simulations for milestones close to the binding site where these interactions are critical for describing the binding/unbinding process.…”

Ligand binding free energy and kinetics calculation in 2020

“…Then, MD calculations are performed to simulate the final part of the binding event . Combined BD‐MD protocols led to interesting results for benzamidine/trypsin and neuraminidase ligands yielding k on and k off values no more than 10‐fold distant from the experimental measure …”