In silico structure based designing of covalent inhibitors against pathogenic kinases

Surekha, P and Eerappa, Rajakumara (2019) In silico structure based designing of covalent inhibitors against pathogenic kinases. Masters thesis, Indian institute of technology Hyderabad.

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Abstract

Kinases are involved in important biological pathways, cell signaling and cell cycle control. Many kinases in pathogenic organisms are responsible for the organism survival and causing infection. Calcium dependent protein kinase (CDPK) is one such kinase present exclusively in apicomplexan parasites. In respond to the calcium signals, these CDPKs get activated and regulate protein secretion, activation of motility, cell invasion and egress. Since humans don’t have CDPKs homolog and are critical for survival of the pathogen, CDPKs acts as a good drug target in diseased conditions. Traditionally available inhibitors are reversible inhibitors; these reversible inhibitors are less potent. On the other hand, covalent inhibitor binds irreversible and form targeted covalent bond with the amino acid residue in the binding pocket. CDPKs don’t have covalent inhibitor. We tried to generate specific reversible and irreversible (covalent) inhibitors against CDPKs by in-silico structure analysis. Using Schrödinger, maestro software derivatives are generated, docked and molecular dynamic simulation studies carried out. The designed covalent inhibitor may be more potent and will have more resident time compare to reversible inhibitors available in the market. Covalent inhibitors may bind stably to the protein and may prevent activation of CDPK even in the presence of calcium signal.

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