The Identification, Analysis and Structure-Based Development of Novel Inhibitors of 6-Hydroxymethyl-7,8-dihydropterin Pyrophosphokinase

Yun MK, et al., 22: 2157-2165, Bioorg & Med Chem, 2014

The microbial folate biosynthetic pathway is commonly known as an ideal target for the development of antimicrobial agents. Both dihydropteroate synthase (DHPS) and 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) are essential enzymes involved in the folate biosynthetic pathway.Authors have previously discovered that a DHPS pterin-pocket inhibitor can also engage the pterin pocket of Francisella tularensis HPPK (FtHPPK). Reported in this current study is the screening of a library of DHPS pterin-pocket binding molecules in order to identify new HPPK inhibitors. Two related compounds were identified as potential inhibitors of HPPK. Using a structure-based approach, a number of variants were synthesized. Binding affinity of those compounds to HPPK were analyzed by surface plasmon resonance (SPR) using a Pall ForteBio Pioneer system. Neutravidin was covalently immobilized onto the surface of the COOH5 sensor chip using standard amine coupling chemistry. Any residual active sites were capped by reaction with ethanolamine. Biotinylated HPPK was injected. Unoccupied biotin-binding sites of neutravidin were capped with amine-PEG2-biotin to minimize non-specific binding of the compounds to be tested. KD values were determined. The structure activity relationships derived from these derivative molecules will contribute greatly for the future design of new HPPK inhibitors.

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