Impdh As A Biological Probe For Rna Antiviral Drug Discovery: Synthesis, Enzymology, Molecular Docking, And Antiviral Activity Of New Ribonucleosides With Surrogate Bases

Abstract

Our interest in the discovery of molecules with antiviral activity against RNA viruses led us to the design of ribonucleosides with surrogate bases with the intent of using inhibition of inosine monophosphate dehydrogenase (IMPDH) as a probe for antiviral drug discovery. A general methodology for the preparation of these compounds is discussed. Kinetic parameters of the inhibition studies with IMPDH, which were carried out spectrophotometrically by monitoring the formation of NADH, are given. Antiviral information and correlation of activity with IMPDH inhibition are discussed.

Keywords:

• IMPDH inhibitors
• synthesis
• antiviral

Acknowledgments

This project was supported by Grant No. AI056540 from the NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. We thank Drs. E. Kern, R. Sidwell, and J. Huggins for antiviral screening results.

Notes

^a K _i = K _i,app /(1 + [IMP])/K _m ).

^bc k _on = k _inact/K _i .