Mycobacterium tuberculosis KasA as a drug target: Structure-based inhibitor design

Abstract

Recent studies have reported the β-ketoacyl-acyl carrier protein KasA as a druggable target for Mycobacterium tuberculosis. This review summarizes the current status of major classes of KasA inhibitors with an emphasis on significant contributions from structure-based design methods leveraging X-ray crystal structures of KasA alone and in complex with inhibitors. The issues addressed within each inhibitor class are discussed while detailing the characterized interactions with KasA and structure-activity relationships. A critical analysis of these findings should lay the foundation for new KasA inhibitors to study the basic biology of M. tuberculosis and to form the basis of new antitubercular molecules of clinical significance with activity against drug-sensitive and drug-resistant infections.

Synthesis, Molecular Docking, Molecular Dynamic Simulation Studies, and Antitubercular Activity Evaluation of Substituted Benzimidazole Derivatives

“…N1-(1H-1,3-benzodiazol-2-yl)-3-chlorobenzene-1,2-diamine (9). Yield: 56%; MP: 95-97 °C; R f : 0.75 (ethyl acetate: hexane, 3 : 1); FT-IR (KBr, cm −1 ): 3387 cm −1 (NH 2 str.…”

“…Te yield ranged from 45 to 78%. Te FTIR, 1 H NMR, and mass spectra of derivatives compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) are given in Supplementary material (Figure S4-S28).…”

“…Moreover, KasA and KasB add two carbons to acyl-AcpM (mycobacterial acyl carrier protein, AcpM) to synthesize ketoacyl-AcpM ( Figure 2 ) although KasA is superior to KasB due to its independence from cultural requirements (nature of genetic disruption growth media). Therefore, KasA protein is chosen over KasB for molecular docking investigations [ 9 ].…”

Advances in computational frameworks in the fight against TB: The way forward

“…A recent review article discusses in detail about the different targets which have been used for ligand screening against TB along with providing a list of websites and repositories from which novel ligands can be retrieved ( Ejalonibu et al, 2021 ). In silico tools which can be used for target identification like, homology modelling, virtual screening, molecular docking, and molecular dynamics simulation to identify druggable targets and lead natural metabolites to fight against M. tuberculosis have also been reviewed in other informative articles ( Okombo and Chibale, 2017 ; Rudraraju et al, 2022 ( Kingdon & Alderwick, 2021 ; Swain and Hussain, 2022)). In one study, M. tuberculosis genes were choosen druggable target to prepare specific compound library from ZINC database, ChEMBL database, and Enamine REAL database for virtual screening.…”

Synthesis, molecular docking, molecular dynamic simulation studies, and anti-tubercular activity evaluation of substituted benzimidazole derivatives

“…In addition, KasA is superior to KasB due to its independence from cultural requirements (nature of genetic disruption growth media). Therefore, KasA protein is chosen over KasB for molecular docking investigations [9]. Substituted benzimidazoles are believed to compromise the bacterial cell wall and cause its mortality.…”