Unravelling the structural interactions between PKR kinase domain and its small molecule inhibitors using computational approaches

作者：Barage Sagar; Kulkarni Abhijeet; Pal Jayanta K; Joshi M****i^*

来源：Journal of Molecular Graphics and Modelling, 2017, 75: 322-329.

DOI：10.1016/j.jmgm.2017.06.009

• PKR
• EIF2AK2
• Inhibitors Docking
• 2-AP
• C16
• Compound 51

The RNA-dependent protein kinase (PKR), an elF2 alpha kinase plays an important role in anti-viral response, apoptosis and cell survival. It is also implicated to play a role in several cancers, metabolic and neurode-generative disorders. A few ATP competitive inhibitors of the PKR have been reported in the literature with promising results in vitro and in vivo. The aim of this study was to unravel the structural interactions between these inhibitors and the PKR kinase domain using molecular simulations and docking. Our study reveals that the reported inhibitors bind in the adenine pocket and form hydrogen bonds with the hinge region and vdW interactions with non-polar residues in the binding site. The most potent inhibitor has several favorable interactions with the binding site and induces the P-loop to fold inward, creating a significant hydrophobic enclosure for itself. The computed binding free energies of these inhibitors are in accord with experimental data (IC50). Strategies to design potent and selective PKR inhibitors are discussed to overcome the reported promiscuity. 2017 Elsevier Inc.

• 出版日期2017-8