Role of Desolvation in Thermodynamics and Kinetics of Ligand Binding to a Kinase

• Published in: Journal of chemical theory and computation Vol. 10; no. 12; pp. 5696 - 5705
• Main Authors: Mondal, Jagannath, Friesner, Richard A, Berne, B. J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 09.12.2014
• ISSN: 1549-9618; 1549-9626
• DOI: 10.1021/ct500584n

Computer simulations are used to determine the free energy landscape for the binding of the anticancer drug Dasatinib to its src kinase receptor and show that before settling into a free energy basin the ligand must surmount a free energy barrier. An analysis based on using both the ligand-pocket separation and the pocket-water occupancy as reaction coordinates shows that the free energy barrier is a result of the free energy cost for almost complete desolvation of the binding pocket. The simulations further show that the barrier is not a result of the reorganization free energy of the binding pocket. Although a continuum solvent model gives the location of free energy minima, it is not able to reproduce the intermediate free energy barrier. Finally, it is shown that a kinetic model for the on rate constant in which the ligand diffuses up to a doorway state and then surmounts the desolvation free energy barrier is consistent with published microsecond time-scale simulations of the ligand binding kinetics for this system [Shaw, D. E. et al. J. Am. Chem. Soc. 2011, 133, 9181−9183 ].