Journal of Petroleum & Environmental Biotechnology

Development of pantothenate synthetase inhibitors for mycobacterium tuberculosis infection: Design and enzyme inhibition studies

Brindha Devi P, Mallika A, Yogeeswari P and Sriram D

: Agrotechnol

Abstract:

Pantothenate synthetase (PS) encoded by panC gene from Mycobacterium tuberculosis a potential target for antituberculosis drugs. PS catalyzes the ATP-dependent condensation of pantoate and ?-alanine to form patothenate in bacteria, yeast and plants. This PS is absent in mammals and both CoA and Acyl carrier protein are essential cofactors for bacterial growth, and hence PS is an attractive chemotherapeutic agent for tuberculosis treatment. The crystal structure of PS were determined from M.tuberculosis and its complexes with AMPCPP, pantoate and pantoyl adenylate. A novel potent PS inhibitors were developed and screened against PS for inhibitory activity. The activity of PS was measured spectrophotometrically through an enzymatic cascade involving myokinase, pyruvate kinase, and lactate dehydrogenase. The rate of PS ATP utilization was quantitated by the reduction of absorbance due to the oxidation of NADH to NAD+ by lactate dehydrogenase, which allowed for an internal control to detect interference from compounds that absorb at 340 nm. This coupled enzymatic reaction was used to screen 100 compounds in a 96-well format. One hundred inhibitory molecules were computationally analyzed using Glide docking, and the inhibitors possessed better binding affinities against the PS enzyme. The in vitro validation of these inhibitors has proved its efficacy as a better target for TB

Biography :

Brindha Devi P has completed his PhD from Andhra University and pursuing research for Ph.D. in the Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Hyderabad Campus.