Quantitative Ranking of Ligand Binding Kinetics with a Multiscale Milestoning Simulation Approach

Abstract

<p>The ranking of small molecule binders by their kinetic (kon and koff) and thermodynamic (delta G) properties can be a valuable metric for lead selection and optimization in a drug discovery campaign, as these quantities are often indicators of in vivo efficacy. Efficient and accurate predictions of these quantities can aid the in drug discovery effort, acting as a screening step. We have previously described a hybrid molecular dynamics, Brownian dynamics, and milestoning model, Simulation Enabled Estimation of Kinetic Rates (SEEKR), that can predict kon’s, koff’s, and G’s. Here we demonstrate the effectiveness of this approach for ranking a series of seven small molecule compounds for the model system, -cyclodextrin, based on predicted kon’s and koff’s. We compare our results using SEEKR to experimentally determined rates as well as rates calculated using long-timescale molecular dynamics simulations and show that SEEKR can effectively rank the compounds by koff and G with reduced computational cost. We also provide a discussion of convergence properties and sensitivities of calculations with SEEKR to establish “best practices” for its future use.</p>

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

“…The model host−guest system β-cyclodextrin with seven different guest molecules was studied (Chart 1), as this was the same system studied with the original SEEKR implementation. Therefore, it was possible to directly compare the accuracy and efficiency of the new MMVT approach to the previous implementation 56 as well as to brute-force MD simulation calculated rates 39 and experimentally measured kinetics. 68−72 System and simulation details can be found in Section S1 of the Supporting Information.…”

An Integrated Markov State Model and Path Metadynamics Approach To Characterize Drug Binding Processes

“…24 However, it has also been recognized that these methods hold great potential in providing an accurate description of drug binding pathways as well as the ability to locate allosteric sites. 24 A convenient trade-off between accuracy and efficiency is provided by SEEKR, 16,17 a hybrid MD/Brownian Dynamics/milestoning methodology 15 suited to efficiently reconstruct on-and off-rates of drug binding processes through a multiscale approach. Conversely, concerning methods more focused on the computational speed, we mention here the scaled MD approach 54 and the closely related τ-RAMD 55 to get fast estimates of drug residence times and unbinding pathways.…”

Predicting Residence Time and Drug Unbinding Pathway through Scaled Molecular Dynamics

“…28 Notably, the SEEKR method introduced by Amaro and co-workers takes advantage of both a multiscale modeling and an highly parallelizable milestoning approach to further improve the sampling efficiency within the atomistic regime. 29,30 Concerning biased-MD approaches, most of them rely on the introduction of external biasing forces acting on selected degrees of freedom (or collective variables). This is the case for umbrella sampling and metadynamics, among many others.…”