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Targeting Kinase Interaction Networks: A New Paradigm In Ppi Based Design Of Kinase Inhibitors

Author(s):

Pranitha Jenardhanan, Manivel Panneerselvam and Premendu P. Mathur*  

Abstract:


Kinases are key modulators in regulating diverse range of cellular activities and are an essential part of the protein-protein interactome. Understanding the interaction of kinases with different substrates and other proteins is vital to decode the cell signaling machinery as well as causative mechanism for disease onset and progression. Most of the designed drugs that target kinases are either conventional ATP mimics that competitively inhibit kinase in activated state or in inactive state, or focused on the catalytic domain. However, the homology of catalytic domains across the kinase class of proteins poses difficulty in the design of target-specific compounds thereby instigating the search and design of compounds that can bind with regions other than ATP/substrate binding domain. Thus understanding the interactome of kinases and residue-residue interaction establishes the communication within the protein and also reveals how the proteins react to the interaction with other macromolecules as well as with small molecule regulators. The inter-residue and intra-residue communication would serve to identify key residues that need to be targeted. Thus the present review discusses briefly the structure and function of few important kinases and highlights the protein-protein interaction (PPI) mechanism of kinases and the kinase specific interactome databases. It focuses on how the protein-protein interfaces and residue based interaction networks are used for the design and development of new potent and target specific drugs.

Keywords:

Human kinome, Kinases, Protein-protein interactions (PPI), peptide inhibitors, peptidomimetics

Affiliation:

Centre for Bioinformatics, Pondicherry University, Puducherry , Department of Biotechnology, BJM School of Biosciences, Indian Institute of Technology Madras, Chennai, Dept. of Biochemistry & Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry



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