Role of Molecular Interactions and Protein Rearrangement in the Dissociation Kinetics of p38α MAP Kinase Type-I/II/III Inhibitors.

ABSTRACT: Understanding the governing factors of fast or slow inhibitor binding/unbinding assists in developing drugs with preferred kinetic properties. For inhibitors with the same binding affinity targeting different binding sites of the same protein, the kinetic behavior can profoundly differ. In this study, we investigated unbinding kinetics and mechanisms of fast (type-I) and slow (type-II/III) binders of p38α mitogen-activated protein kinase, where the crystal structures showed that type-I and type-II/III inhibitors bind to pockets with different conformations of the Asp-Phe-Gly (DFG) motif. The work used methods that combine conventional molecular dynamics (MD), accelerated molecular dynamics (AMD) simulations, and the newly developed pathway search guided by internal motions (PSIM) method to

SUBMITTER: You W 

PROVIDER: S-EPMC5975198 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature