Molecular Simulations of Solved Co-crystallized X-Ray Structures Identify Action Mechanisms of PDE? Inhibitors.

ABSTRACT: PDE? is a small protein that binds and controls the trafficking of RAS subfamily proteins. Its inhibition protects initiation of RAS signaling, and it is one of the common targets considered for oncological drug development. In this study, we used solved x-ray structures of inhibitor-bound PDE? targets to investigate mechanisms of action of six independent all-atom MD simulations. An analysis of atomic simulations combined with the molecular mechanic-Poisson-Boltzmann solvent accessible surface area/generalized Born solvent accessible surface area calculations led to the identification of action mechanisms for a panel of novel PDE? inhibitors. To the best of our knowledge, this study is one of the first in silico investigations on co-crystallized PDE? protein. A detailed atomic-scale understanding of the molecular mechanism of PDE? inhibition may assist in the design of novel PDE? inhibitors. One of the most common side effects for diverse small molecules/kinase inhibitors is their off-target interactions with cardiac ion channels and human-ether-a-go-go channel specifically. Thus, all of the studied PDE? inhibitors are also screened in silico at the central cavities of hERG1 potassium channels.

SUBMITTER: Salmas RE 

PROVIDER: S-EPMC4576317 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature