Article
Simulation of ligand dissociation kinetics from the protein kinase PYK2
Computational Chemistry
(2022)
Abstract
Early-stage drug discovery projects often focus on equilibrium binding affinity to the target alongside selectivity and other pharmaceutical properties. The kinetics of drug binding are ignored but can have significant influence on drug efficacy. Therefore, increasing attention has been paid on evaluating drug-binding kinetics early in a drug discovery process. Simulating drug-binding kinetics at the atomic level is challenging for the long time scale involved. Here, we used the transition-based reweighting analysis method (TRAM) with the Markov state model to study the dissociation of a ligand from the protein kinase PYK2. TRAM combines biased and unbiased simulations to reduce computational costs. This work used the umbrella sampling technique for the biased simulations. Although using the potential of mean force from umbrella sampling simulations with the transition-state theory over-estimated the dissociation rate by three orders of magnitude, TRAM gave a dissociation rate within an order of magnitude of the experimental value.
Keywords
- drug-binding kinetics,
- PYK2,
- transition-based reweighting analysis method,
- umbrella sampling
Disciplines
Publication Date
October 30, 2022
DOI
10.1002/jcc.26991
Citation Information
Justin Spiriti, Frank Noe and Chung Wong. "Simulation of ligand dissociation kinetics from the protein kinase PYK2" Computational Chemistry Vol. 43 Iss. 28 (2022) Available at: http://works.bepress.com/chung-wong/86/