Molecular docking, 3D-QSAR studies of indole hydrazone as Staphylococcus aureus pyruvate kinase inhibitor

Author : Srilata Ballu, Ramesh Itteboina, Sree Kanth Sivan, Vijjulatha Manga

Staphylococcus aureus is a bacterium that is a common cause of skin infection, respiratory disease and food poisoning. Pyruvate kinase is an enzyme involved in glycolysis. Inhibition of pyruvate kinase initiates reverse sequence of glycolysis that is lethal for bacterium. Docking and 3D quantitative structure activity relationship (3D-QSAR) studies were performed on 46 Indole hydrazone derivatives reported as inhibitors of Pyruvate kinase. Ligands were built and docked into protein active site using GLIDE 5.6. The docked poses were analyzed and the best docked poses were selected for further 3D-QSAR analysis using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methodology. QSAR models were generated using 35 molecules in the training set. Developed models showed good statistical reliability which is evident from r2ncv and r2loo values. The predictive ability of these models was determined using a test set of 11 molecules that gave acceptable predictive correlation (r2Pred) values. CoMFA models provide the most significant correlation of steric and electrostatic fields with biological activities. CoMSIA model provides a correlation of steric, electrostatic, acceptor, donor and hydrophobic fields with biological activities. The information rendered 3D QSAR model initiated us to optimize the lead and design new potential inhibitors.

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