inhibitory activity toward Mtb PDF. Also, the Mtb PDF contains highly conserved
motifs, EGCLS and QHEXXH (where X is any hydrophobic amino acid), which
are important for the metal ion coordination and thus necessary for its enzyme
activity. A number of Mtb PDF inhibitors are reported till date by knowing the 3D
structure-based mechanism or HTS techniques [63–65].
Another important druggable target in Mtb protein synthesis mechanism is aspartyl tRNA synthetase (AspS), which represents a key molecular target for
designing anti-TB agents [66]. Soto et al. recently identified a couple of inhibitors,
GSK97C (spiro-oxazolidin-2-one), GSK93A (2-amino-1,3-thiazole), GSK85A, and
GSK92A (enamides) targeting Mtb AspS using a whole cell-target-based approach
[67]. The X-ray crystal structure of Mycobacterium smegmatis AspS is already
being reported and the catalytic site consisting of three important amino acid
residues, Asp 174, Phe521, and Thr565 which will further aid in structure-based
drug discovery process [66]. Leucyl–tRNA synthetase (LeuRS) which functions in
protein synthesis represents another potent druggable target in Mtb. The compound,
GSK-070, an oxaborole derivative, is demonstrated to inhibit LeuRS and consequently blocks the protein synthesis by forming a complex with tRNA and trapping
the enzyme–tRNA complex on the editing site. GSK-070 has recently completed
Phase I clinical trial [68, 69].
2.4 Molecular Targets in Mtb Energy Production
and Metabolism
Key druggable target in energy metabolism includes Cytochrome b subunit of the
cytochrome bc1 complex (Qcrb) of Mtb which is mainly involved in the respiratory transport chain for ATP synthesis [70]. HTS campaign identified novel
imidazo [1,2-a] pyridine inhibitors and Q203 compound as a potential clinical
candidate for Mtb therapy [71]. However, this compound is bacteriostatic and does
not kill dormant bacteria. Further, homology modeling and docking study of Qcrb
with Q203 inhibitor was performed by Choi and Ko to elucidate the drug–target
molecular mechanism of action. Parish et al. discovered benzimidazoles of phenyl
alkyl groups showing good anti-mycobacterial intracellular activity in the
nanomolar range targeting Qcrb protein, with promising sterilizing activity and low
cytotoxicity against eukaryotic cells. This study further paved way for the molecular mechanism of action of small-molecule inhibitor against Qcrb inhibition [72].
Isocitrate lyase is the first enzyme of the glyoxylate shunt pathway involved in the
Mtb carbon metabolism by cleaving isocitrate to succinate and glyoxylate. This
enzyme is critical in Mtb for its replication and persistence, shown in in vivo mouse
model [73, 74].
Malate synthase (GlcB) is the second enzyme of the Mtb carbon metabolism
and anaplerosis with catalytic conversion from glyoxylate to malate and
acetyl-coenzyme A (acetyl-CoA) into CoA, respectively. Crystal structure of GlcB
Impact of Target-Based Drug Design in Anti-bacterial …
319
motifs, EGCLS and QHEXXH (where X is any hydrophobic amino acid), which
are important for the metal ion coordination and thus necessary for its enzyme
activity. A number of Mtb PDF inhibitors are reported till date by knowing the 3D
structure-based mechanism or HTS techniques [63–65].
Another important druggable target in Mtb protein synthesis mechanism is aspartyl tRNA synthetase (AspS), which represents a key molecular target for
designing anti-TB agents [66]. Soto et al. recently identified a couple of inhibitors,
GSK97C (spiro-oxazolidin-2-one), GSK93A (2-amino-1,3-thiazole), GSK85A, and
GSK92A (enamides) targeting Mtb AspS using a whole cell-target-based approach
[67]. The X-ray crystal structure of Mycobacterium smegmatis AspS is already
being reported and the catalytic site consisting of three important amino acid
residues, Asp 174, Phe521, and Thr565 which will further aid in structure-based
drug discovery process [66]. Leucyl–tRNA synthetase (LeuRS) which functions in
protein synthesis represents another potent druggable target in Mtb. The compound,
GSK-070, an oxaborole derivative, is demonstrated to inhibit LeuRS and consequently blocks the protein synthesis by forming a complex with tRNA and trapping
the enzyme–tRNA complex on the editing site. GSK-070 has recently completed
Phase I clinical trial [68, 69].
2.4 Molecular Targets in Mtb Energy Production
and Metabolism
Key druggable target in energy metabolism includes Cytochrome b subunit of the
cytochrome bc1 complex (Qcrb) of Mtb which is mainly involved in the respiratory transport chain for ATP synthesis [70]. HTS campaign identified novel
imidazo [1,2-a] pyridine inhibitors and Q203 compound as a potential clinical
candidate for Mtb therapy [71]. However, this compound is bacteriostatic and does
not kill dormant bacteria. Further, homology modeling and docking study of Qcrb
with Q203 inhibitor was performed by Choi and Ko to elucidate the drug–target
molecular mechanism of action. Parish et al. discovered benzimidazoles of phenyl
alkyl groups showing good anti-mycobacterial intracellular activity in the
nanomolar range targeting Qcrb protein, with promising sterilizing activity and low
cytotoxicity against eukaryotic cells. This study further paved way for the molecular mechanism of action of small-molecule inhibitor against Qcrb inhibition [72].
Isocitrate lyase is the first enzyme of the glyoxylate shunt pathway involved in the
Mtb carbon metabolism by cleaving isocitrate to succinate and glyoxylate. This
enzyme is critical in Mtb for its replication and persistence, shown in in vivo mouse
model [73, 74].
Malate synthase (GlcB) is the second enzyme of the Mtb carbon metabolism
and anaplerosis with catalytic conversion from glyoxylate to malate and
acetyl-coenzyme A (acetyl-CoA) into CoA, respectively. Crystal structure of GlcB
Impact of Target-Based Drug Design in Anti-bacterial …
319