Decaprenylphosphoryl-β-D-ribose-oxidase (DprE1), a subunit of the essential decaprenylphosphoribose-2'-epimerase, plays a crucial role in the synthesis of cell wall arabinan components in mycobacteria, including the pathogen responsible for tuberculosis, Mycobacterium tuberculosis. In this study, we designed, synthesised, and evaluated 15 (BOK-1-BOK-10 and BOP-1-BOP-5) potential inhibitors of DprE1 from a series of 1,2,3-triazole ligands using a validated DprE1 inhibition assay. Two compounds, BOK-2 and BOK-3, demonstrated significant inhibition with IC50 values of 2.2 ± 0.1 and 3.0 ± 0.6 μM, respectively, whereas the standard drug (TCA-1) showed inhibition at 3.0 ± 0.2 μM. Through molecular modelling and dynamic simulations, we explored the structural relationships between selected 1,2,3-triazole compounds and DprE1, revealing key features for effective drug-target interactions. This study introduces a novel approach for designing ligands against DprE1, offering a potential therapeutic strategy for tuberculosis treatment.
Keywords: 1,2,3-triazoles; DprE1 inhibitor assay; Tuberculosis.
Identification of 15 (BOK-1–BOK-10 and BOP-1–BOP-5) potent inhibitors of DprE1 enzyme from 1,2,3-triazole ligands.BOK-2 and BOK-3 exhibited significant DprE1 inhibition with IC50 values of 2.2 ± 0.1 and 3.0 ± 0.6 μM, respectively.Molecular modelling and dynamic simulations elucidated key structural features for effective drug–target interactions.Novel approach introduced for designing DprE1 ligands, potentially aiding tuberculosis treatment.Findings offer promising candidates for future tuberculosis research.