1.5 Å resolutions in complex with a covalent inhibitor. This structure revealed an
alpha-/beta-hydrolase polypeptide fold and a catalytic triad formed by three amino
acid residues, Ser 124, Glu 228, and His 260 [28, 29]. Kovac et al. discovered few
sulfonate inhibitors against Ag85C protein based on the catalytic mechanism of
action elucidated by its crystal structure and potent compound discovered having
promising activity of IC 50 = 4.3 lM using the mycolyltransferase inhibition assay
[30]. Ag85B in complex with trehalose crystal structure was solved by Anderson
et al. to study the structure-based anti-tubercular drug design aspects of understanding its interface mechanisms [31].
The building block of mycolic acid biosynthesis in Mtb is controlled by an essential
carboxyltransferase enzyme, AccD6, which is involved in the synthesis of
malonyl-CoA by the catalysis of acetyl-CoA [32]. The crystal structure of Mtb AccD6
in complex with haloxyfop-R, a herbicide targeting plant acetyl-CoA carboxylases,
revealed its molecular basis of inhibitor binding leading to the development of novel
herbicides with better ADMET profile as Mtb AccD6 inhibitors [33]. Other druggable
target of Mtb cellular growth includes PimA, and the target is proven by different
research groups using in vitro and in vivo techniques [34]. PimA takes part in the
biosynthesis of phosphatidyl-myoinositol mannosides. Thus, it could be used as
potent in silico/in vitro target-based HTS program for the TB therapy [34].
2.1.2 Peptidoglycan Biosynthesis Pathway Targets
Gram-positive and Gram-negative bacteria cell walls have unique biopolymer PG,
which is necessary for keeping its cellular integrity. The Mtb cell wall possesses key
druggable Mur ligases—MurA, MurC, MurD, MurE, and MurF, which are
essential for biosynthesis of bacterial PG and not present in the mammalian system
[35]. Mur proteins are conserved among different bacterial species and also possess
a common three-dimensional (3D) structural motif [38]. Structure–function relationship studies on Mtb-MurB oxidoreductase enzyme were performed in our
laboratory by an integrated approach involving multiple sequence alignment
(MSA), homology modeling, molecular dynamics, molecular electrostatic potential
surface (MEPS) mapping, and molecular docking studies. In order to understand the
sequence conservation, MSA among different mycobacterium Mtb, Escherichia coli
and Staphylococcus aureus MurB proteins showed that Tyr122, Gly123, Arg156,
Arg218, and Ser237 residues are conserved among these microbes (Fig. 5a).
The binding analysis of the natural ligand naphthyl tetronic acid toward Mtb and
E. coli-MurB is presented in Fig. 5b–d. Molecular docking studies using different
chemical classes of well-known 28 MurB inhibitors belonging to 3,5-dioxopyrazolidine
derivatives showed hydrogen bonding and other week interactions with these MtbMurB residues for the development of broad-spectrum anti-bacterial drug. Further, our
computational binding affinity showed good correlation of 0.83 with its experimental
IC 50 value. This binding study with most potent compound 10a also supported the
experimental site-directed mutational studies on key functional Mtb-MurB residues and
is presented in Table 2 [37].
Impact of Target-Based Drug Design in Anti-bacterial …
315
alpha-/beta-hydrolase polypeptide fold and a catalytic triad formed by three amino
acid residues, Ser 124, Glu 228, and His 260 [28, 29]. Kovac et al. discovered few
sulfonate inhibitors against Ag85C protein based on the catalytic mechanism of
action elucidated by its crystal structure and potent compound discovered having
promising activity of IC 50 = 4.3 lM using the mycolyltransferase inhibition assay
[30]. Ag85B in complex with trehalose crystal structure was solved by Anderson
et al. to study the structure-based anti-tubercular drug design aspects of understanding its interface mechanisms [31].
The building block of mycolic acid biosynthesis in Mtb is controlled by an essential
carboxyltransferase enzyme, AccD6, which is involved in the synthesis of
malonyl-CoA by the catalysis of acetyl-CoA [32]. The crystal structure of Mtb AccD6
in complex with haloxyfop-R, a herbicide targeting plant acetyl-CoA carboxylases,
revealed its molecular basis of inhibitor binding leading to the development of novel
herbicides with better ADMET profile as Mtb AccD6 inhibitors [33]. Other druggable
target of Mtb cellular growth includes PimA, and the target is proven by different
research groups using in vitro and in vivo techniques [34]. PimA takes part in the
biosynthesis of phosphatidyl-myoinositol mannosides. Thus, it could be used as
potent in silico/in vitro target-based HTS program for the TB therapy [34].
2.1.2 Peptidoglycan Biosynthesis Pathway Targets
Gram-positive and Gram-negative bacteria cell walls have unique biopolymer PG,
which is necessary for keeping its cellular integrity. The Mtb cell wall possesses key
druggable Mur ligases—MurA, MurC, MurD, MurE, and MurF, which are
essential for biosynthesis of bacterial PG and not present in the mammalian system
[35]. Mur proteins are conserved among different bacterial species and also possess
a common three-dimensional (3D) structural motif [38]. Structure–function relationship studies on Mtb-MurB oxidoreductase enzyme were performed in our
laboratory by an integrated approach involving multiple sequence alignment
(MSA), homology modeling, molecular dynamics, molecular electrostatic potential
surface (MEPS) mapping, and molecular docking studies. In order to understand the
sequence conservation, MSA among different mycobacterium Mtb, Escherichia coli
and Staphylococcus aureus MurB proteins showed that Tyr122, Gly123, Arg156,
Arg218, and Ser237 residues are conserved among these microbes (Fig. 5a).
The binding analysis of the natural ligand naphthyl tetronic acid toward Mtb and
E. coli-MurB is presented in Fig. 5b–d. Molecular docking studies using different
chemical classes of well-known 28 MurB inhibitors belonging to 3,5-dioxopyrazolidine
derivatives showed hydrogen bonding and other week interactions with these MtbMurB residues for the development of broad-spectrum anti-bacterial drug. Further, our
computational binding affinity showed good correlation of 0.83 with its experimental
IC 50 value. This binding study with most potent compound 10a also supported the
experimental site-directed mutational studies on key functional Mtb-MurB residues and
is presented in Table 2 [37].
Impact of Target-Based Drug Design in Anti-bacterial …
315