Identification of Druggable Kinase Target Conformations Using Markov Model Metastable States Analysis of apo-Abl.

ABSTRACT: Kinases are important targets for drug development. However, accounting for the impact of possible structural rearrangements on the binding of kinase inhibitors is complicated by the extensive flexibility of their catalytic domain. The dynamic N-lobe contains four particular mobile structural elements: the Asp-Phe-Gly (DFG) motif, the phosphate (P) positioning loop, the activation (A) loop, and the αC helix. In our previous study [Meng et al. J. Chem. Theory Comput. 2018 14, 2721-2732], we combined various simulation techniques with Markov state modeling (MSM) to explore the free energy landscape of Abl kinase beyond conformations that are known from X-ray crystallography. Here we examine the resulting Markov model in greater detail by analyzing its metastable states. A characteriza

SUBMITTER: Paul F 

PROVIDER: S-EPMC7398592 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature