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

Efficient prediction and ranking of small molecule binders by their kinetic (k_on and k_off) and thermodynamic (ΔG) properties can be a valuable metric for drug lead optimization, as these quantities are often indicators of in vivo efficacy. We have previously described a hybrid molecular dynamics, Brownian dynamics, and milestoning model, Simulation Enabled Estimation of Kinetic Rates (SEEKR), that can predict k_on’s, k_off’s, and ΔG’s. Here we demonstrate the effectiveness of this approach for ranking a series of seven small molecule compounds for the model system, β-cyclodextrin, based on predicted k_on’s and k_off’s. We compare our results using SEEKR to experimentally determined rates as well as rates calculated using long time scale molecular dynamics simulations and show that SEEKR can effectively rank the compounds by k_off and ΔG 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.