Target Identification in Anti-Tuberculosis Drug Discovery

Abstract

Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis (TB), a disease that, although preventable and curable, remains a global epidemic due to the emergence of resistance and a latent form responsible for a long period of treatment. Drug discovery in TB is a challenging task due to the heterogeneity of the disease, the emergence of resistance, and uncomplete knowledge of the pathophysiology of the disease. The limited permeability of the cell wall and the presence of multiple efflux pumps remain a major barrier to achieve effective intracellular drug accumulation. While the complete genome sequence of Mtb has been determined and several potential protein targets have been validated, the lack of adequate models for in vitro and in vivo studies is a limiting factor in TB drug discovery programs. In current therapeutic regimens, less than 0.5% of bacterial proteins are targeted during the biosynthesis of the cell wall and the energetic metabolism of two of the most important processes exploited for TB chemotherapeutics. This review provides an overview on the current challenges in TB drug discovery and emerging Mtb druggable proteins, and explains how chemical probes for protein profiling enabled the identification of new targets and biomarkers, paving the way to disruptive therapeutic regimens and diagnostic tools.

Computational approaches: Atom-based 3D-QSAR, molecular docking, ADME-Tox, MD simulation and DFT to find novel multi-targeted Anti-tubercular agents

“…Mycobacterial cell wall is composed of polysaccharide arabinogalactan, which is synthesised through DprE1 enzyme mediated redox reaction. During the reaction the oxidase enzyme DprE1 carried out conversion of decaprenylphosphoryl-dribose (DPR) to decaprenylphosphoryl-d-arabinose (DPA) by epimerization via an intermediate decaprenylphosphoryl-2-keto-β-derythro-pentofuranose (DPX) [23][24][25]. Inhibition of DprE1 disrupts the synthesis of arabinogalactan, weakening the bacterial cell wall and making the bacteria more susceptible towards the chemotherapeutic agents used for the treatment of MTB, MDR-TB and XDR-TB [26].…”

1,3-Proton Transfer of Pyridoxal 5′-Phosphate Schiff Base in the Branched-Chain Aminotransferase: Concerted or Stepwise Mechanism?

“…Therefore, it is crucial to develop more effective and less toxic drugs to effectively treat TB patients. 2 Branched-chain aminotransferases (BCAT) is essential for the growth and survival of the bacteria. 3,4 As a result, BCAT in Mtb known as MtIlvE, has emerged as a promising target for the development of antituberculosis drugs.…”

“…Great efforts have been made to design and discover antituberculosis drugs; however, the effectiveness of most drugs against Mt b is hindered by drug resistance. Therefore, it is crucial to develop more effective and less toxic drugs to effectively treat TB patients …”