2D-QSAR, Docking Studies, and In Silico ADMET Prediction of Polyphenolic Acetates as Substrates for Protein Acetyltransferase Function of Glutamine Synthetase of Mycobacterium tuberculosis
A novel transacetylase (TAase) function of glutamine synthetase (GS) in bacterial species such as Mycobacterium smegmatis and Mycobacterium tuberculosis H37Rv was established by us, termed as mycobacterial TAase (MTAase). Several polyphenolic acetates (PAs) were found to be substrates for MTAase by inhibiting certain receptor proteins such as glutathione S-transferase by way of acetylation. The present work describes the descriptor-based 2D-QSAR studies developed for a series of PA synthesized by us and evaluated for MTAase and antimycobacterial activity using stepwise multiple linear regression method with the kinetic constants and the minimum inhibitory constant (MIC) as the dependent variables, to address the fact that TAase activity was leading to the antimycobacterial activity. Further, blind docking methods using AutoDock were carried out to study the interaction of potent PA with the crystal structure of M. tuberculosis GS. PAs were predicted to bind M. tuberculosis GS on the protein surface away from the known active site of GS. Subsequent focussed/refined docking of potent PA with GS showed that the -amino group of Lys4 of GS formed a cation- interaction with the benzene ring of PA. Also, ADMET-related descriptors were calculated to predict the pharmacokinetic properties for the selection of the effective and bioavailable compounds. 1. Introduction Our laboratory is credited for the discovery of novel TAase which catalyzes the possible transfer of acetyl group from PA to certain functional proteins such as GST, cytochrome P-450 reductase, and nitric oxide synthase (NOS) leading to their functional modifications [1–3]. An assay procedure was developed utilizing the inhibition of cytosolic GST brought about by TAase-catalyzed acetylation by PA. Both the substrates, namely, the target protein GST and the acetyl group donor PAs were found to take part in the TAase-catalyzed bimolecular reaction [2]. This assay procedure was utilized to purify TAase from tissues like human placenta and rat liver and characterized as calreticulin, a calcium-binding ER luminal protein [4, 5]. The acetylation of receptor proteins such as GST and NOS at ε-amino group lysine residues was established by immunoblotting using acetylated lysine antibody and mass spectrometry [6, 7]. Recently, TAase was identified and established by us in bacterial species such as Mycobacterium smegmatis [8] and Mycobacterium tuberculosis (Mtb) H37Rv [9] as glutamine synthetase (GS). Glutamine synthetase catalyzes the conversion of glutamate to glutamine in the presence of ammonium ion with
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