title: Unbinding Kinetics of a p38 MAP Kinase Type II Inhibitor from Metadynamics Simulations.
abstract: 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.
authors.affiliation: Computational Biomedicine (IAS-5/INM-9), Forschungszentrum Jülich , Jülich 52425, Germany.
authors.forename: Rodrigo
authors.identifier: 0000-0002-7102-1840
authors.initials: R
authors.lastname: Casasnovas
authors.affiliation: Università della Svizzera Italiana (USI) , Faculty of Informatics, Institute of Computational Science - Center for Computational Medicine in Cardiology, via G. Buffi 13, CH-6900, Lugano, Switzerland.|Department of Pharmacy, University of Naples "Federico II" , via D. Montesano 49, Naples I-80131, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
authors.affiliation: Department of Chemistry, Columbia University , New York, New York, 10027, United States.
authors.forename: Pratyush
authors.initials: P
authors.lastname: Tiwary
authors.affiliation: Computational Biomedicine (IAS-5/INM-9), Forschungszentrum Jülich , Jülich 52425, Germany.
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zurich, and Faculty of Informatics, Institute of Computational Science, Università della Svizzera Italiana , via G. Buffi 13, Lugano CH-6900, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: Parrinello
mesh_terms: D007700:Kinetics; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D014508:Urea; D048051:p38 Mitogen-Activated Protein Kinases