%0 Journal Article %1 Casasnovas2017p38FullUnbindingMetadynamics %A Casasnovas, Rodrigo %A Limongelli, Vittorio %A Tiwary, Pratyush %A Carloni, Paolo %A Parrinello, Michele %D 2017 %J Journal of the American Chemical Society %K enhanced-sampling important kinetic-drug-design ligand-unbinding metadynamics molecular-dynamics p38 residence-time unbinding-kinetics unbinding-pathways %P 4780-4788 %R 10.1021/jacs.6b12950 %T Unbinding kinetics of a p38 MAP kinase type II inhibitor from metadynamics simulations %U http://dx.doi.org/10.1021/jacs.6b12950 %V 139 %X Understanding the structural and energetic requisites of ligand binding towards its molecular target is of paramount relevance in drug design. In the 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 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.

@article{Casasnovas2017p38FullUnbindingMetadynamics, abstract = { Understanding the structural and energetic requisites of ligand binding towards its molecular target is of paramount relevance in drug design. In the 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 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. }, added-at = {2017-03-15T20:09:44.000+0100}, author = {Casasnovas, Rodrigo and Limongelli, Vittorio and Tiwary, Pratyush and Carloni, Paolo and Parrinello, Michele}, biburl = {https://www.bibsonomy.org/bibtex/20015672e3af956c27a5a2f43eed3b703/salotz}, description = {Unbinding kinetics of a p38 MAP kinase type II inhibitor from metadynamics simulations - Journal of the American Chemical Society (ACS Publications)}, doi = {10.1021/jacs.6b12950}, eprint = {http://dx.doi.org/10.1021/jacs.6b12950}, interhash = {93e8e319c0094bc43882ec12b43ff70c}, intrahash = {0015672e3af956c27a5a2f43eed3b703}, journal = {Journal of the American Chemical Society}, keywords = {enhanced-sampling important kinetic-drug-design ligand-unbinding metadynamics molecular-dynamics p38 residence-time unbinding-kinetics unbinding-pathways}, note = {PMID: 28290199}, pages = {4780-4788}, timestamp = {2017-08-10T04:29:38.000+0200}, title = {Unbinding kinetics of a p38 MAP kinase type II inhibitor from metadynamics simulations}, url = {http://dx.doi.org/10.1021/jacs.6b12950}, volume = 139, year = 2017 }