Application of crystallographic and modeling methods in the design of purine nucleoside phosphorylase inhibitors.
Competitive inhibitors of the salvage pathway enzyme purine-nucleoside phosphorylase (purine-nucleoside:orthophosphate ribosyltransferase, EC 2.4.2.1) have been designed by using the three-dimensional structure of the enzyme as determined by x-ray crystallography. The process was an iterative one that utilized interactive computer graphics, Monte Carlo-based conformational searching, energy minimization, and x-ray crystallography. The proposed compounds were synthesized and tested by an in vitro assay. Among the compounds designed and synthesized are the most potent competitive inhibitors of purine nucleoside phosphorylase thus far reported.
Ealick
S E
SE
University of Alabama, Birmingham 35294.
Babu
Y S
YS
Bugg
C E
CE
Erion
M D
MD
Guida
W C
WC
Montgomery
J A
JA
Secrist
J A
JA
D000595:Amino Acid Sequence; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D009010:Monte Carlo Method; D011487:Protein Conformation; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014961:X-Ray Diffraction
D004791:Enzyme Inhibitors; D011683:Purine-Nucleoside Phosphorylase