Identification of Novel Potent Inhibitors for ATP-Phosphoribosyl Transferase Using Three-Dimensional Structural Database Search Technique

Abstract

We identified new potent inhibitors for ATP-phosphoribosyl transferase, which is the first enzyme in histidine biosynthesis pathway, using three-dimensional database search (3D-search) technique. The 3D-search was based on the structure of product molecule, N-1-(5 0 -phosphoribosyl)-ATP, as a template to find molecules targeting to the binding sites of two substrates (ATP and 5 0 -phosphoribosyl-1-pyrophosphate), i.e., bi-substrate mimicking. Four commercially-available compounds with three different chemical classes were examined out of 36 low-molecular weight compounds selected from the hits of the searches.Amino-(chlorophenyl)-triazolopyrimidine compounds, which are the simplest and smallest ones, showed potent activity (e.g., 92% inhibition at 100 mM). The structural comparison with the product molecule suggests that the simultaneous occupation of two substrate-binding sites likely enhances the enzyme inhibition. The most potent compound examined in this study was a disulfide-bond containing molecule (IC 50 ¼ 50 nM), whose mode of action seems to be different from the others. Further studies using its derivatives were carried out for clarification.

Discovery of Novel Nitrobenzothiazole Inhibitors for Mycobacterium tuberculosis ATP Phosphoribosyl Transferase (HisG) through Virtual Screening

“…Pentachlorophenol, dicoumarol, and 2,4-dinitrophenol have all been shown to have moderate inhibition strengths, with K i ’s in the range of 50−400 μM against the E. coli enzyme . Three-dimensional pharmacophore searching was used to identify biaryl inhibitors of Arabidopsis thaliana HisG, the most potent of which was a di(amino-naphthyl)-disulfide with an IC 50 of 50 nM . In this study, we report the results of a virtual screen for novel inhibitors for HisG.…”

“…14 Three-dimensional pharmacophore searching was used to identify biaryl inhibitors of Arabidopsis thaliana HisG, the most potent of which was a di(amino-naphthyl)-disulfide with an IC 50 of 50 nM. 15 In this study, we report the results of a virtual screen for novel inhibitors for HisG. An initial screen yielded several hits that had significant inhibition in an in vitro assay, with IC 50 's in the 1-10 µM range.…”