The main challenge in the anti-TB drug discovery program is the different types
of screening compounds using virtual, cell-based, and target-based in vitro methods
lack the important Mtb physiology in which its cell wall permeability, metabolic
stability, and druggable target’s resistance are often neglected. While maintaining
the compound efficacy, these unique properties are difficult to achieve for its success toward TB drug discovery. Thus, in silico and in vitro biochemical techniques
should provide guidance for the compound to be selective and specific with respect
to particular druggable targets under different physiologically appropriate conditions. This in turn can avoid compounds with unfavorable physicochemical as well
pharmacokinetics and pharmacodynamic properties. Further, the study will progress
by identifying new hits having novel scaffolds for drug development and new
protein targets, showing promising mechanism of action from the existing knowledge on drugs and its resistance mechanisms.
The structure-guided inhibitor designing is performed based on the structure of
the molecular targets. Due to the advances in X-ray crystallographic techniques,
many mycobacterial protein targets have been crystallized, solved, and deposited in
the PDB. If the crystal structure of a target protein is not solved experimentally
using X-ray crystallography or NMR, homology modeling can be done to build
predictive model of the protein using a crystal structure of related proteins with a
good sequence identity. The 3D structures of the molecular targets provide an
understating of protein folding, function and active site regions that are important
aspects in the anti-tubercular drug discovery process. The druggable molecular
target in Mtb for which the crystal structure is submitted in the PDB is given in
Table 3. In addition to crystal coordinates of the target proteins, the interactions
with known inhibitors are also crucial for the structure-based inhibitor designing.
The binding mode of these compounds/drugs toward the well-characterized
molecular target aids the effective drug discovery process. Another notable advance
in structure-based drug designing is the drug repurposing/reprofiling strategy which
is described below.
Conventionally, the discovery and development of anti-bacterial agents were
based on the identification of novel compounds targeting various bacterial targets.
This process of finding novel compounds is exceptionally expensive and takes an
enormous amount of time. Only a few compounds pass the clinical trials with good
safety profiles among thousands of compounds tested, which makes the drug discovery and development process very time-consuming and expensive [117]. In the
last few years, a number of new anti-TB agents have been proposed and developed
into effective therapeutics; some of them were obtained by modifying the already
existing drugs or scaffolds, and many are developed by repurposing strategy [118].
Drug repurposing or repositioning is a discovery process, which takes drugs that
have been approved for one disease and repositioning them for another disease
[118–124]. The traditional drug discovery and development process takes enormous amount of time to reach into market. However, discovering new indications
for already approved drugs can improve the drug safety and can lower the development cost and time. Many repurposed drugs are being used nowadays for the
treatment of various diseases. Also drug repurposing is becoming very popular in
324
A. C. Pushkaran et al.
of screening compounds using virtual, cell-based, and target-based in vitro methods
lack the important Mtb physiology in which its cell wall permeability, metabolic
stability, and druggable target’s resistance are often neglected. While maintaining
the compound efficacy, these unique properties are difficult to achieve for its success toward TB drug discovery. Thus, in silico and in vitro biochemical techniques
should provide guidance for the compound to be selective and specific with respect
to particular druggable targets under different physiologically appropriate conditions. This in turn can avoid compounds with unfavorable physicochemical as well
pharmacokinetics and pharmacodynamic properties. Further, the study will progress
by identifying new hits having novel scaffolds for drug development and new
protein targets, showing promising mechanism of action from the existing knowledge on drugs and its resistance mechanisms.
The structure-guided inhibitor designing is performed based on the structure of
the molecular targets. Due to the advances in X-ray crystallographic techniques,
many mycobacterial protein targets have been crystallized, solved, and deposited in
the PDB. If the crystal structure of a target protein is not solved experimentally
using X-ray crystallography or NMR, homology modeling can be done to build
predictive model of the protein using a crystal structure of related proteins with a
good sequence identity. The 3D structures of the molecular targets provide an
understating of protein folding, function and active site regions that are important
aspects in the anti-tubercular drug discovery process. The druggable molecular
target in Mtb for which the crystal structure is submitted in the PDB is given in
Table 3. In addition to crystal coordinates of the target proteins, the interactions
with known inhibitors are also crucial for the structure-based inhibitor designing.
The binding mode of these compounds/drugs toward the well-characterized
molecular target aids the effective drug discovery process. Another notable advance
in structure-based drug designing is the drug repurposing/reprofiling strategy which
is described below.
Conventionally, the discovery and development of anti-bacterial agents were
based on the identification of novel compounds targeting various bacterial targets.
This process of finding novel compounds is exceptionally expensive and takes an
enormous amount of time. Only a few compounds pass the clinical trials with good
safety profiles among thousands of compounds tested, which makes the drug discovery and development process very time-consuming and expensive [117]. In the
last few years, a number of new anti-TB agents have been proposed and developed
into effective therapeutics; some of them were obtained by modifying the already
existing drugs or scaffolds, and many are developed by repurposing strategy [118].
Drug repurposing or repositioning is a discovery process, which takes drugs that
have been approved for one disease and repositioning them for another disease
[118–124]. The traditional drug discovery and development process takes enormous amount of time to reach into market. However, discovering new indications
for already approved drugs can improve the drug safety and can lower the development cost and time. Many repurposed drugs are being used nowadays for the
treatment of various diseases. Also drug repurposing is becoming very popular in
324
A. C. Pushkaran et al.