Structure-based drug design: inhibitors of purine nucleoside phosphorylase.

The three-dimensional structure of the salvage pathway enzyme purine nucleoside phosphorylase (EC 2.4.2.1) as determined by X-ray crystallography has been used to design inhibitors of the enzyme. The design process is an iterative one utilizing X-ray crystallographic analysis, interactive computer graphics, Monte Carlo-based conformational searching, and energy minimization. The proposed compounds were synthesized, their IC50 values for inhibition of the enzyme determined, and the structures of their complexes with PNP analyzed by X-ray analysis. This procedure has led to the discovery of the most potent membrane-permeable competitive inhibitors of this enzyme thus far reported.