Clarithromycin: It is a semisynthetic macrolide antibiotic, which is approved to
treat various skin as well as respiratory tract infections. The drug binds reversibly to
the bacterial 23S rRNA of 50S ribosomal subunit and impedes the amino acid
translocation and further protein assembly. Clarithromycin is also used to treat
nontuberculous mycobacterial infections [133]. Several studies have been conducted
from the mid-90s to study the effect of Clarithromycin on Mtb. Clarithromycin gets
metabolized into 14-hydroxyclarithromycin; both of them act synergistically [134].
Cavalieri et al. reported that clarithromycin/14-hydroxyclarithromycin had considerably improved the in vitro anti-mycobacterial activities of the conventional TB
drugs, Isoniazid, Rifampicin, and Ethambutol against MDR bacilli [135].
Fluoroquinolones: Fluoroquinolones are one of the broad-spectrum antibiotic
classes effective against both Gram-negative and Gram-positive bacteria. They kill
the bacteria by preventing the bacterial DNA replication. The third-generation
Levofloxacin and the fourth-generation Moxifloxacin and Gatifloxacin are now
used as second-line anti-TB drugs for treating drug-resistant strains of Mtb [136,
137].
Linezolid: It is a synthetic antibiotic belonging to the class of oxazolidinone.
Linezolid is used to treat Gram-positive bacterial infections. Linezolid functions by
binding to the peptidyl transferase center located in the 23S portion of 50S ribosome, thereby inhibiting protein synthesis. The bactericidal activity of Linezolid
against drug-resistant Mtb has been well studied in the past few years, and now, it is
being used as a second-line TB drug in MDR and XDR-TB treatment regimen
[136]. But there were concerns against its safety and tolerability [138].
Chlorpromazine: It is an FDA-approved drug used to treat psychotic disorders
such as schizophrenia. Chlorpromazine showed in vitro anti-tuberculous activity by
inhibiting NADH:menaquinone oxidoreductase enzyme [139]. Also, it is shown to
improve the efficacy of the first-line anti-TB drugs in combination with
Chlorpromazine [140, 141].
4 Recent Computer-Aided Drug Design Approaches
for Anti-TB Drug Discovery
The advances in the computational methods and techniques have a great impact on
the drug discovery and development. The effectiveness of computational algorithms
and software tools has tremendous impact on speeding up the conventional drug
discovery. Now, computational techniques are inseparable part of drug discovery
and development process. Traditionally, the computer-aided drug discovery process
involves virtual screening (VS) of a set of small molecules against the X-ray crystal
structures. If the crystal structure data is not available, ligand-based drug designing
uses knowledge of existing active compounds against a particular target proteins. In
ligand-based inhibitor designing, using the structural features of the known ligands
of druggable molecular targets, new compound with improved potency can be
330
A. C. Pushkaran et al.
treat various skin as well as respiratory tract infections. The drug binds reversibly to
the bacterial 23S rRNA of 50S ribosomal subunit and impedes the amino acid
translocation and further protein assembly. Clarithromycin is also used to treat
nontuberculous mycobacterial infections [133]. Several studies have been conducted
from the mid-90s to study the effect of Clarithromycin on Mtb. Clarithromycin gets
metabolized into 14-hydroxyclarithromycin; both of them act synergistically [134].
Cavalieri et al. reported that clarithromycin/14-hydroxyclarithromycin had considerably improved the in vitro anti-mycobacterial activities of the conventional TB
drugs, Isoniazid, Rifampicin, and Ethambutol against MDR bacilli [135].
Fluoroquinolones: Fluoroquinolones are one of the broad-spectrum antibiotic
classes effective against both Gram-negative and Gram-positive bacteria. They kill
the bacteria by preventing the bacterial DNA replication. The third-generation
Levofloxacin and the fourth-generation Moxifloxacin and Gatifloxacin are now
used as second-line anti-TB drugs for treating drug-resistant strains of Mtb [136,
137].
Linezolid: It is a synthetic antibiotic belonging to the class of oxazolidinone.
Linezolid is used to treat Gram-positive bacterial infections. Linezolid functions by
binding to the peptidyl transferase center located in the 23S portion of 50S ribosome, thereby inhibiting protein synthesis. The bactericidal activity of Linezolid
against drug-resistant Mtb has been well studied in the past few years, and now, it is
being used as a second-line TB drug in MDR and XDR-TB treatment regimen
[136]. But there were concerns against its safety and tolerability [138].
Chlorpromazine: It is an FDA-approved drug used to treat psychotic disorders
such as schizophrenia. Chlorpromazine showed in vitro anti-tuberculous activity by
inhibiting NADH:menaquinone oxidoreductase enzyme [139]. Also, it is shown to
improve the efficacy of the first-line anti-TB drugs in combination with
Chlorpromazine [140, 141].
4 Recent Computer-Aided Drug Design Approaches
for Anti-TB Drug Discovery
The advances in the computational methods and techniques have a great impact on
the drug discovery and development. The effectiveness of computational algorithms
and software tools has tremendous impact on speeding up the conventional drug
discovery. Now, computational techniques are inseparable part of drug discovery
and development process. Traditionally, the computer-aided drug discovery process
involves virtual screening (VS) of a set of small molecules against the X-ray crystal
structures. If the crystal structure data is not available, ligand-based drug designing
uses knowledge of existing active compounds against a particular target proteins. In
ligand-based inhibitor designing, using the structural features of the known ligands
of druggable molecular targets, new compound with improved potency can be
330
A. C. Pushkaran et al.