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.
Biocryst Pharmaceuticals, Inc, Birmingham, Alabama 35244.
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JA
Montgomery
D000818:Animals; D003460:Crystallization; D015195:Drug Design; D005583:Fourier Analysis; D007288:Inosine / Q000097:blood; D009010:Monte Carlo Method; D011487:Protein Conformation; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D007288:Inosine; D011683:Purine-Nucleoside Phosphorylase