Biophysical and Computational Landscapes of Mycobacterial Pyrophosphatase: A Closer View of Drug Repurposing With Different Natural and Synthetic Compounds.

Abstract Mycobacterial pyrophosphatase (Mt-ppa) play essential role in bacterial in vitro and in vivo survival. This family of proteins reacts on pyrophosphates to release orthophosphates and protect bacteria from pyrophosphates toxicity. Rv3628 encodes pyrophosphate protein which is a type I pyrophosphate protein. This protein is engaged in hydrolysis of tri and diphosphates (majorly GTP, ATP and GDP) and its catalysis is metal ion dependent. Mt-ppa was showed efficient interaction with GTP molecule, whose Kd was 37.9µM, ΔH was -11Kcal/mol and ΔG was -6.06Kcal/mol. The protein was interacted with ATP family genes that resemble that it is participator in conversion of diphosphates moiety to the residual monophosphates. W102G, V150G, F44G, I119G, L93F, F3G, F122G, I108G, L32G, M82G, Y17G, L59G, V5G, V26G, I7G, W140D, W140G, W140A, F80G, W140S, L49G, L56G, I9G, V60G, V19G, V92G, L28G, L61G, Y126E and F123G are the top 30 mutation hits and Y126G, Y42G, R30G, E8G, K16G are top mutational hits in active site of Mt-ppa. Mt-ppa is temperature and pH sensitive as increasing temperature and pH decreases protein stability. It is also the receptor for several kinases that phosphorylate this protein at different Ser/Thr/Tyr sites. Virtual screening of 700 compounds from herbal ingredient targets (HITs) subset of zinc database give ZINC000003979028, ZINC000003870413, ZINC000003870412, ZINC000150338758, ZINC0000070450948, ZINC000150338754, ZINC000095098891, ZINC000000119985, ZINC000005085286 as the top target hits and Mac0182344 and NAV_2729 as the top GTPase inhibitor that can target and hinders Mt-ppa activity.