Document Type
Article
Keywords
focal adhesion kinase, drug-binding kinetics, free energy methods, umbrella sampling, steered molecular dynamics
Abstract
Most early-stage drug discovery projects focus on equilibrium binding affinity to the target alongside selectivity and other pharmaceutical properties. Since many approved drugs have nonequilibrium binding characteristics, there has been increasing interest in optimizing binding kinetics early in the drug discovery process. As focal adhesion kinase (FAK) is an important drug target, we examine whether steered molecular dynamics (SMD) can be useful for identifying drug candidates with the desired drug-binding kinetics. In simulating the dissociation of 14 ligands from FAK, we find an empirical power–law relationship between the simulated time needed for ligand unbinding and the experimental rate constant for dissociation, with a strong correlation depending on the SMD force used. To improve predictions, we further develop regression models connecting experimental dissociation rate with various structural and energetic quantities derived from the simulations. These models can be used to predict dissociation rates from FAK for related compounds.
Publication Date
January 2021
Publication Title
Life
Volume
11
Issue
2
DOI
10.3390/life11020074
Recommended Citation
Spiriti, Justin and Wong, Chung, "Qualitative Prediction of Ligand Dissociation Kinetics from Focal Adhesion Kinase Using Steered Molecular Dynamics" (2021). Chemistry & Biochemistry Faculty Works. 72.
DOI: https://doi.org/10.3390/life11020074
Available at:
https://irl.umsl.edu/chemistry-faculty/72