TY - JOUR
T1 - Structure-activity relationship mediated molecular insights of DprE1 inhibitors
T2 - A Comprehensive Review
AU - Dash, Swagatika
AU - Rathi, Ekta
AU - Kumar, Avinash
AU - Chawla, Kiran
AU - Joseph, Alex
AU - Kini, Suvarna G.
N1 - Funding Information:
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.
Publisher Copyright:
© 2023 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
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U2 - 10.1080/07391102.2023.2230312
DO - 10.1080/07391102.2023.2230312
M3 - Review article
C2 - 37395797
AN - SCOPUS:85164427059
SN - 0739-1102
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
ER -
