ChemRxiv
These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
1/1
2 files

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

preprint
submitted on 12.05.2020 and posted on 12.05.2020 by Benjamin Jagger, Anupam Anand Ojha, Rommie Amaro

Accurate and efficient computational predictions of ligand binding kinetics can be useful to inform drug discovery campaigns, particularly in the screening and lead optimization phases. Simulation Enabled Estimation of Kinetic Rates, SEEKR, is a multiscale molecular dynamics, Brownian dynamics, and milestoning simulation approach for calculating receptor-ligand association and dissociation rates. Here we present the implementation of a Markovian milestoning with Voronoi tessellations approach that significantly reduces the simulation cost of calculations as well as further improving their parallelizability. The new approach is applied to a host-guest system to assess its effectiveness for rank-ordering compounds by kinetic rates and to the model protein system, trypsin, with the noncovalent inhibitor benzamidine. For both applications, we demonstrate that the new approach requires up to a factor of 10 less simulation time to achieve results with comparable or increased accuracy.

Funding

NIH T32-GM008326

NIH P41 GM103426

NIH DP2 OD007237

History

Email Address of Submitting Author

bjager@ucsd.edu

Institution

University of California San Diego

Country

United States

ORCID For Submitting Author

0000-0003-2958-3695

Declaration of Conflict of Interest

No conflict of interests to declare

Version Notes

Submitted version, 8-May 2020

Exports