Introduction
The development of drug resistance is a severe threat to public health.
Presently, use of antibiotics targets bacterial structure and essential
functions. Due to the well-identified anti-mycobacterial resistance,
there has been an increased interest in the discovery of novel drugs to
target other essential processes of bacterial survival. Currently,
target-based drug screening is promising and efficient way for
development of therapeutic agents. In recent years, extensive efforts
have been made for the discovery of inhibitors of enzymes involved in
the biosynthesis of aromatic amino acids. One such well-recognised
pathway is shikimic acid pathway consisting of seven enzymatic reactions
responsible for the production of chorismate; a precursor for essential
amino acids. Among seven enzymes, the most valuable target is Shikimate
Kinase (SK). Inhibition of this enzyme is fatal for M.
tuberculosis (Mtb ).1 SK inhibitors offer
potential for development of new anti-tubercular drugs that are
selective for Mtb since mammals do not have Shikimate pathway
enzymes necessary for de novo synthesis of essential amino
acids. MTSK belongs to the family of nucleoside monophosphate
(NMP) kinases and consist of 3 domains: LID (LD), CORE (CD), and
substrate binding (SBD) domains.2, 3
Owing to the importance of this enzyme, structural based virtual
screening of compounds from institute library was done where S-014-1049
was found to be active against SK and against the mycobacteria in
culture as well. This compound specifically binds to the CD of the
enzyme which was primarily confirmed during the docking studies and
further by validating with the mutants.It is a polyphenol and derivative
of curcumin. In some recent studies a few polyphenols were found active
against Mtb which also have many health
benefits.4 The biological and pharmacological
properties make polyphenols a valuable druggable molecule
.5, 6 In one of our previous studies, we found an
existing polyphenolic PKC-δ inhibitor, Rottlerin to be active against
mycobacteria where it significantly inhibited SK activity and has been
used as positive control in this study.7Therefore,
compound S-014-1049 could be a promising drug candidate for further
development