hypoxic conditions. The interactions with the hydrophobic pockets consisting of
Val 49, Val 123, Val 128, and Ile 171 contribute to the specificity of the compound
as compared to other known GyrB inhibitors. Another, notable amino acid residues
at the active site regions include Asp 79, Arg 82, and Arg 141 obtained from GyrB
crystal structure [96]. Later, a couple of studies also reported novel classes of
compounds targeting Mtb GyrB through molecular hybridization studies followed
by protein–ligand molecular docking [97–99]. More recently, VS studies have been
conducted for a group of flavonoid compounds to identify a dual inhibitor for DNA
gyrase and isoleucyl-tRNA synthetase enzymes. The binding of the high-ranked
flavonoid, taxifolin, to both these enzymes was validated through molecular
dynamics simulation. Further, anti-mycobacterial activity of taxifolin was evaluated
using a cell viability assay resulted in MIC
12.5 lg/ml against Mtb [100].
Another notable Mtb target is RNA polymerase enzyme (RNAP), which is
required for the transcription process. RNAP is the target for the first-line anti-TB
drug Rifampicin. An MDR and XDR strain of Mtb is resistant to Rifampicin due to
the mutations in the rpoB gene encoding RNAP. Rifampicin-resistant Mtb strains
show mutation in the 81 bp hotspot region of rpoB gene, stretching from codons
507 to 533 [101]. Researchers are underway to identify derivatives of Rifampicin
which are not affected by rpoB mutations in the binding site of Rifampicin. Lin
et al. recently solved the X-ray crystal structure of RNAP in its ligand free form as
well as in complex with Rifampicin at 3.8–4.4 Å resolution. They identified novel
compounds Na-aroyl-N-aryl-phenylalaninamides (AAPs) by HTS and solved the
crystal structure of RNAP-AAPs complexes. Further, they showed binding to a
different site than Rifampicin in the mycobacterial RNAP. Hence, mutations at the
Rifampicin binding site will not hamper AAPs activity. Also, AAPs showed
addictive anti-mycobacterial activity in combination with Rifampicin [102].
More recently, new anti-bacterial target in Mtb RNAP has been reported by
Wang et al. They constructed phylogenetic trees for 17 genes important for the
functioning of RNAP enzyme in 13 different mycobacterial species and identified
positive selection sites or conserved regions. They modeled the 3D structure of
RNAP and performed molecular docking calculations with anti-bacterial drugs. By
comparing the positive selection site and as well as molecular interaction, they
proposed a putative drug binding site near Cys 933 and His 935 residues on the
rpoB subunit [103]. Several research groups are underway to identify novel inhibitors against Mtb RNAP as well as to identify potential Rifampicin analogues
effective against MDR and XDR strains of TB [104, 105].
2.7 Other Druggable Targets of Mtb
Filamenting temperature-sensitive protein Z (FtsZ) is a cytoskeletal protein
involved in the Mtb cell division. The protein forms a contractile ring structure
(Z ring) at the site of cell division. FtsZ also functions to recruit cell division
proteins to the septum required for the formation of new cell wall between dividing
322
A. C. Pushkaran et al.
Val 49, Val 123, Val 128, and Ile 171 contribute to the specificity of the compound
as compared to other known GyrB inhibitors. Another, notable amino acid residues
at the active site regions include Asp 79, Arg 82, and Arg 141 obtained from GyrB
crystal structure [96]. Later, a couple of studies also reported novel classes of
compounds targeting Mtb GyrB through molecular hybridization studies followed
by protein–ligand molecular docking [97–99]. More recently, VS studies have been
conducted for a group of flavonoid compounds to identify a dual inhibitor for DNA
gyrase and isoleucyl-tRNA synthetase enzymes. The binding of the high-ranked
flavonoid, taxifolin, to both these enzymes was validated through molecular
dynamics simulation. Further, anti-mycobacterial activity of taxifolin was evaluated
using a cell viability assay resulted in MIC
12.5 lg/ml against Mtb [100].
Another notable Mtb target is RNA polymerase enzyme (RNAP), which is
required for the transcription process. RNAP is the target for the first-line anti-TB
drug Rifampicin. An MDR and XDR strain of Mtb is resistant to Rifampicin due to
the mutations in the rpoB gene encoding RNAP. Rifampicin-resistant Mtb strains
show mutation in the 81 bp hotspot region of rpoB gene, stretching from codons
507 to 533 [101]. Researchers are underway to identify derivatives of Rifampicin
which are not affected by rpoB mutations in the binding site of Rifampicin. Lin
et al. recently solved the X-ray crystal structure of RNAP in its ligand free form as
well as in complex with Rifampicin at 3.8–4.4 Å resolution. They identified novel
compounds Na-aroyl-N-aryl-phenylalaninamides (AAPs) by HTS and solved the
crystal structure of RNAP-AAPs complexes. Further, they showed binding to a
different site than Rifampicin in the mycobacterial RNAP. Hence, mutations at the
Rifampicin binding site will not hamper AAPs activity. Also, AAPs showed
addictive anti-mycobacterial activity in combination with Rifampicin [102].
More recently, new anti-bacterial target in Mtb RNAP has been reported by
Wang et al. They constructed phylogenetic trees for 17 genes important for the
functioning of RNAP enzyme in 13 different mycobacterial species and identified
positive selection sites or conserved regions. They modeled the 3D structure of
RNAP and performed molecular docking calculations with anti-bacterial drugs. By
comparing the positive selection site and as well as molecular interaction, they
proposed a putative drug binding site near Cys 933 and His 935 residues on the
rpoB subunit [103]. Several research groups are underway to identify novel inhibitors against Mtb RNAP as well as to identify potential Rifampicin analogues
effective against MDR and XDR strains of TB [104, 105].
2.7 Other Druggable Targets of Mtb
Filamenting temperature-sensitive protein Z (FtsZ) is a cytoskeletal protein
involved in the Mtb cell division. The protein forms a contractile ring structure
(Z ring) at the site of cell division. FtsZ also functions to recruit cell division
proteins to the septum required for the formation of new cell wall between dividing
322
A. C. Pushkaran et al.