Mapping the ribonucleolytic active site of bovine seminal ribonuclease. The binding of pyrimidinyl phosphonucleotide inhibitors

作者：Dossi Kyriaki; Tsirkone Vicky G; Hayes Joseph M; Matousek Josef^*; Pouckova Pavla; Soucek Josef; Zadinova Marie; Zographos Spyros E; Leonidas Demetres D

来源：European Journal of Medicinal Chemistry, 2009, 44(11): 4496-4508.

DOI：10.1016/j.ejmech.2009.06.039

• Bovine seminal ribonuclease
• Enzyme inhibition
• Drug design QikProp
• ADME properties

Bovine seminal ribonuclease (BS-RNase) is a 27 kDa homodimeric enzyme and a member of the pancreatic RNase A superfamily. It is the only RNase with a quaternary structure and it is a mixture of two dimeric forms. In the most abundant form the active site is formed by the swapping of the N-terminal segments. BS-RNase is a potent antitumor agent with severe side effects such as aspermatogenicity, and immunosuppression. As a first step towards the design of potent inhibitors of this enzyme we mapped its active site through the study of the binding of uridine 2'-phosphate (U2'p), uridine T-phosphate (U3'p), uridine 5'-diphosphate (UDP), cytidine T-phosphate (C3'p), and cytidine 5-phosphate (C5'p), by kinetics, and Xray crystallography. These phosphonucleotides are potent inhibitors with C3'p being the most potent with a K-i value of 22 mu M. Absorption, distribution, metabolism, and excretion pharmacokinetic property predictions reveal U2'p, U3'p, and C5'p as the most promising with respect to oral bioavailability. In vivo studies on the aspermatogenic effect have shown that C3'p and C5'p inhibit significantly this biological action of BS-RNase.

• 出版日期2009-11