Identification of novel potent inhibitors for ATP-phosphoribosyl transferase using three-dimensional structural database search technique

We identified new potent inhibitors for ATP-phosphoribosyl transferase, whi ch is the first enzyme in histidine biosynthesis pathway, using three-dimen sional database search (3D-search) technique. The 3D-search was based on th e structure of product molecule, N-1-(5'-phosphoribosyl)-ATP, as a template to find molecules targeting to the binding sites of two substrates (ATP an d 5'-phosphoribosyl-1-pyrophosphate), i.e., bi-substrate mimicking. Four co mmercially-available compounds with three different chemical classes were e xamined 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% inhibitio n at 100 muM). The structural comparison with the product molecule suggests that the simultaneous occupation of two substrate-binding sites likely enh ances the enzyme inhibition. The most potent compound examined in this stud y was a disulfide-bond containing molecule (IC50 = 50 nM), whose mode of ac tion seems to be different from the others. Further studies using its deriv atives were carried out for clarification.