Structure-activity relationship mediated molecular insights of DprE1 inhibitors: A Comprehensive Review

Abstract

Emerging threats of multi-drug resistant (MDR), extensively drug-resistant (XDR), and totally drug-resistant (TDR) tuberculosis led to the discovery of a novel target which was entitled Decaprenylphosphoryl-β-D-ribose 2’-epimerase (DprE1) enzyme. DprE1 is composed of two isoforms, decaprenylphosphoryl-β-D-ribose oxidase (DprE1) and decaprenylphosphoryl-D-2-keto erythro pentose reductase (DprE2). The enzymes, DprE1 and DprE2, regulate the two-step epimerization process to form DPA (Decaprenylphosphoryl arabinose) from DPX (Decaprenylphosphoryl-D-ribose), which is the sole precursor in the cell wall synthesis of arabinogalactan (AG) and lipoarabinomannan (LAM). Target-based and whole-cell-based screening played an imperative role in the identification of the druggable target, DprE1, whereas the druggability of the DprE2 enzyme is not proved yet. To date, diverse scaffolds of heterocyclic and aromatic ring systems have been reported as DprE1 inhibitors based on their interaction mode, i.e. covalent, and non-covalent inhibitors. This review describes the structure-activity relationship (SAR) of reported covalent and non-covalent inhibitors to enlighten about the crucial pharmacophoric features required for DprE1 inhibition, along with in-silico studies which characterize the amino acid residues responsible for covalent and non-covalent interactions.

Communicated by Ramaswamy H. Sarma

Keywords:

• Mycobacterium tuberculosis
• DprE1
• covalent and non-covalent inhibitors
• multi-drug resistance
• anti-tubercular

Acknowledgment

Swagatika Dash is thankful to the Manipal Academy of Higher Education, MAHE, Manipal, for the Dr. T.M.A. Pai Doctoral Fellowship. The authors would like to acknowledge the Manipal-Schrödinger Centre for Molecular Simulations, Manipal Academy of Higher Education, and Manipal College of Pharmaceutical Sciences for providing the necessary support and facilities for research. The authors also would like to acknowledge ChemDraw and BioRender.Com.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The author(s) reported no funding associated with the work featured in this article.