The Diverse Binding Modes Explain the Nanomolar Levels of Inhibitory Activities Against 1-Deoxy-d-Xylulose 5-Phosphate Reductoisomerase from <i>Plasmodium falciparum</i> Exhibited by Reverse Hydroxamate Analogs of Fosmidomycin with Varying <i>N</i>-Substituents.

ABSTRACT: It is established that reverse hydroxamate analogs of fosmidomycin inhibit the growth of Plasmodium falciparum by inhibiting 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), the second enzyme of the non-mevalonate pathway, which is absent in humans. Recent biochemical studies have demonstrated that novel reverse fosmidomycin analogs with phenylalkyl substituents at the hydroxamate nitrogen exhibit inhibitory activities against PfDXR at the nanomolar level. Moreover, crystallographic analyses have revealed that the phenyl moiety of the N-phenylpropyl substituent is accommodated in a previously unidentified subpocket within the active site of PfDXR. In this study, the crystal structures of PfDXR in complex with a series of reverse N-phenylalkyl

SUBMITTER: Takada S 

PROVIDER: S-EPMC11721986 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature