TY  - JOUR
AU  - Casasnovas, Rodrigo
AU  - Limongelli, Vittorio
AU  - Tiwary, Pratyush
AU  - Carloni, Paolo
AU  - Parrinello, Michele
TI  - Unbinding Kinetics of a p38 MAP Kinase Type II Inhibitor from Metadynamics Simulations
JO  - Journal of the American Chemical Society
VL  - 139
IS  - 13
SN  - 1520-5126
CY  - Washington, DC
PB  - American Chemical Society
M1  - FZJ-2017-03090
SP  - 4780 - 4788
PY  - 2017
AB  - Understanding the structural and energetic requisites of ligand binding toward its molecular target is of paramount relevance in drug design. In recent years, atomistic free energy calculations have proven to be a valid tool to complement experiments in characterizing the thermodynamic and kinetic properties of protein/ligand interaction. Here, we investigate, through a recently developed metadynamics-based protocol, the unbinding mechanism of an inhibitor of the pharmacologically relevant target p38 MAP kinase. We provide a thorough description of the ligand unbinding pathway identifying the most stable binding mode and other thermodynamically relevant poses. From our simulations, we estimated the unbinding rate as koff = 0.020 ± 0.011 s–1. This is in good agreement with the experimental value (koff = 0.14 s–1). Next, we developed a Markov state model that allowed identifying the rate-limiting step of the ligand unbinding process. Our calculations further show that the solvation of the ligand and that of the active site play crucial roles in the unbinding process. This study paves the way to investigations on the unbinding dynamics of more complex p38 inhibitors and other pharmacologically relevant inhibitors in general, demonstrating that metadynamics can be a powerful tool in designing new drugs with engineered binding/unbinding kinetics.
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000398764000030
C6  - pmid:28290199
DO  - DOI:10.1021/jacs.6b12950
UR  - https://juser.fz-juelich.de/record/829377
ER  -