active in in vivo murine TB model [160]. An oxazolidinone class of compounds
Sutezolid, Delpazolid, TBI-223, and Contezolid are in the various phases of clinical
trials for TB. These compounds inhibit protein synthesis in Mtb [161–163]. The
benzothiazinone class of compounds, BTZ-043 and Macozinone, is demonstrated
to inhibit the DprE1 enzyme of mycobacteria leading to the inhibition of arabinogalactan synthesis. Both these compounds are now in Phase 1 clinical trials.
The development of vaccines against Mtb has also been of interest by several
research groups. H56 vaccine is in clinical trials, which is a multistage vaccination
strategy consisting of a combination of early antigen Ag85B and early secretary
antigen target (ESAT-6) with Rv2660c protein, which is associated with latency.
The vaccine is demonstrated to promote T-cell response, and it is also controlled by
the reactivation of the bacilli [164].
6 Future Directions to TB Drug Discovery Process
With the availability of validated Mtb molecular targets by the knowledge of the
complete genome sequence of Mtb H37Rv, target-based discovery of new inhibitors is gaining interest in which the target modeling and chemoinformatics
approaches have played a pivotal role. Host-directed therapies are also reported in
recent years, which mainly focus on boosting the immune system of the host.
Recently, pharmaceutical chemists have been pushing the discipline beyond
computer-aided drug design in the field of chemical biology, to study and manipulate the biological systems at the system level. In the small-molecule drug discovery program, HTS campaigns using in silico and in vitro techniques are of
paramount importance for the hit to lead identification. In addition, a recent trend in
the preclinical campaign includes fragment-based drug discovery process, which
includes focused or specific screening and iterative screening. This has been coupled with the speed and automation of a number of in silico (pipeline pilot mode)
and biophysical techniques, which has the capacity to measure quantitatively the
direct interaction between small molecule and druggable protein of interest. The
application of computational and biophysical techniques demonstrates the direct
target engagement with its hits or small molecules, which in turn increases the
confidence in the HTS campaign.
During TB drug development program, different metrics were adopted in optimizing the hits to lead to compound discovery with an ultimate goal of decreasing
the late-stage attrition in the clinical trials. The disease-driven biochemical pathways and sometimes the complex target space associated with this at the tissue level
lead to new developments in the TB drug discovery process. This involves
small-molecule library design to complex physiological models, which would in
turn mimic the target tissue in the TB disease model system [165]. In the present
scenario, the heterogeneous TB cellular models are studied thoroughly to understand variety of phenotypes and its 3D cellular imaging. These in turn occupy the
bigger dataset. The informatics and algorithms for computing and analysis these big
Impact of Target-Based Drug Design in Anti-bacterial …
333
Sutezolid, Delpazolid, TBI-223, and Contezolid are in the various phases of clinical
trials for TB. These compounds inhibit protein synthesis in Mtb [161–163]. The
benzothiazinone class of compounds, BTZ-043 and Macozinone, is demonstrated
to inhibit the DprE1 enzyme of mycobacteria leading to the inhibition of arabinogalactan synthesis. Both these compounds are now in Phase 1 clinical trials.
The development of vaccines against Mtb has also been of interest by several
research groups. H56 vaccine is in clinical trials, which is a multistage vaccination
strategy consisting of a combination of early antigen Ag85B and early secretary
antigen target (ESAT-6) with Rv2660c protein, which is associated with latency.
The vaccine is demonstrated to promote T-cell response, and it is also controlled by
the reactivation of the bacilli [164].
6 Future Directions to TB Drug Discovery Process
With the availability of validated Mtb molecular targets by the knowledge of the
complete genome sequence of Mtb H37Rv, target-based discovery of new inhibitors is gaining interest in which the target modeling and chemoinformatics
approaches have played a pivotal role. Host-directed therapies are also reported in
recent years, which mainly focus on boosting the immune system of the host.
Recently, pharmaceutical chemists have been pushing the discipline beyond
computer-aided drug design in the field of chemical biology, to study and manipulate the biological systems at the system level. In the small-molecule drug discovery program, HTS campaigns using in silico and in vitro techniques are of
paramount importance for the hit to lead identification. In addition, a recent trend in
the preclinical campaign includes fragment-based drug discovery process, which
includes focused or specific screening and iterative screening. This has been coupled with the speed and automation of a number of in silico (pipeline pilot mode)
and biophysical techniques, which has the capacity to measure quantitatively the
direct interaction between small molecule and druggable protein of interest. The
application of computational and biophysical techniques demonstrates the direct
target engagement with its hits or small molecules, which in turn increases the
confidence in the HTS campaign.
During TB drug development program, different metrics were adopted in optimizing the hits to lead to compound discovery with an ultimate goal of decreasing
the late-stage attrition in the clinical trials. The disease-driven biochemical pathways and sometimes the complex target space associated with this at the tissue level
lead to new developments in the TB drug discovery process. This involves
small-molecule library design to complex physiological models, which would in
turn mimic the target tissue in the TB disease model system [165]. In the present
scenario, the heterogeneous TB cellular models are studied thoroughly to understand variety of phenotypes and its 3D cellular imaging. These in turn occupy the
bigger dataset. The informatics and algorithms for computing and analysis these big
Impact of Target-Based Drug Design in Anti-bacterial …
333