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′-phosphoribosyl)-ATP, as a template to find molecules targeting to the binding sites of two substrates (ATP and 5′-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 μM). 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 (IC50=50 nM), whose mode of action seems to be different from the others. Further studies using its derivatives were carried out for clarification.