5′-Modified pyrimidine nucleosides as inhibitors of ribonuclease A

Four 5′-deoxy-5′-nipecotic acid substituted pyrimidine nucleosides were synthesized and characterized. Their inhibitory activities towards ribonuclease A (RNase A) have been studied by enzyme kinetics and docking experiments. All inhibition constants obtained were in the sub-millimolar range. Biochemical analysis shows that the uridine derivative is more potent than the corresponding thymidine derivatives and that the inhibition is competitive in nature. For thymidine derivatives, the 3′-hydroxy group plays an important role in binding as well as in inhibition. Docking studies also support the experimental results. In the docking conformation the uridine derivative was found to bind to the P1P2 subsite with the acid group within hydrogen bonding distance of the active site histidine residues.

Inhibition of the ribonucleolytic activity of ribonuclease A by 5’-modified pyrimidine nucleosides having free carboxyl groups is reported for the first time.Figure optionsDownload as PowerPoint slide