Identification of a pyrimidinetrione derivative as the potent DprE1 inhibitor by structure-based virtual ligand screening

Abstract

Despite the increasing need of new antituberculosis drugs, the number of agents approved for the market has fallen to an all-time low. In response to the emerging drug resistance followed, structurally unique chemical entities will be highlighted. decaprenylphosphoryl-β-d-ribose oxidase (DprE1) participating in the biosynthesis of mycobacterium cell wall is a highly vulnerable and validated antituberculosis target. On the basis of it, a systematic strategy was applied to identify a high-quality lead compound (compound 50) that inhibits the essential enzyme DprE1, thus blocking the synthesis of the mycobacterial cell wall to kill M. tuberculosis in vitro and in vivo. Correspondingly, the rational design and synthetic strategy for compound 50 was reported. Notably, the compound 50 has been confirmed to be no toxicity. Altogether, our data suggest the compound 50 targeting DprE1 is a promising candidate for the tuberculosis (TB) therapy.

Keywords: DprE1; Pyrimidinetrione; Tuberculosis; Virtual ligand screening; Zinc database.