Journal Article

FZJ-2017-03090

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Unbinding Kinetics of a p38 MAP Kinase Type II Inhibitor from Metadynamics Simulations

Casasnovas, R. ; Limongelli, V. ; Tiwary, P. ; Carloni, P. (Corresponding author)FZJ* ; Parrinello, M. (Corresponding author)

2017
American Chemical Society Washington, DC

This record in other databases:      

Please use a persistent id in citations: doi:10.1021/jacs.6b12950

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.

---

Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Computational Biomedicine (INM-9)

Research Program(s):

1. 574 - Theory, modelling and simulation (POF3-574) (POF3-574)

Appears in the scientific report 2017

---

Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; No Authors Fulltext ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

---