Inhibitor design for ribonuclease A: the binding of two 5'-phosphate uridine analogues.
In the quest for the rational design of selective and potent inhibitors for members of the pancreatic ribonuclease A (RNase A) family of biomedical interest, the binding of uridine 5'-phosphate (U5P) and uridine 5'-diphosphate (UDP) to RNase A have been investigated using kinetic studies and X-ray crystallography. Both nucleotides are competitive inhibitors of the enzyme, with K(i) values of 4.0 and 0.65 mM, respectively. They bind to the active site of the enzyme by anchoring two molecules connected to each other by hydrogen bonds and van der Waals interactions. While the first of the inhibitor molecules binds with its nucleobase in the pyrimidinyl-binding subsite, the second is bound at the purine-preferring subsite. The unexpected binding of a pyrimidine at the purine-binding subsite has added new important elements to the rational design approach for the discovery of new potent inhibitors of the RNase A superfamily.
Tsirkone
Vicky G
VG
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 11635 Athens, Greece.
Dossi
Kyriaki
K
Drakou
Christina
C
Zographos
Spyros E
SE
Kontou
Maria
M
Leonidas
Demetres D
DD
D000818:Animals; D002417:Cattle; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006860:Hydrogen Bonding / Q000187:drug effects; D008958:Models, Molecular; D012259:Ribonuclease, Pancreatic / Q000037:antagonists & inhibitors*; D055672:Static Electricity; D040681:Structural Homology, Protein; D014500:Uracil Nucleotides / Q000378:metabolism*; D014530:Uridine Diphosphate / Q000378:metabolism
D004791:Enzyme Inhibitors; D014500:Uracil Nucleotides; D014530:Uridine Diphosphate; D012259:Ribonuclease, Pancreatic