Rational Optimization of Mechanism-Based Inhibitors through Determination of the Microscopic Rate Constants of Inactivation

Carter G. Eiden, Kimberly M. Maize, Barry C. Finzel, John D. Lipscomb, Courtney C. Aldrich

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Mechanism-based inhibitors (MBIs) are widely employed in chemistry, biology, and medicine because of their exquisite specificity and sustained duration of inhibition. Optimization of MBIs is complicated because of time-dependent inhibition resulting from multistep inactivation mechanisms. The global kinetic parameters kinact and KI have been used to characterize MBIs, but they provide far less information than is commonly assumed, as shown by derivation and simulation of these parameters. We illustrate an alternative and more rigorous approach for MBI characterization through determination of the individual microscopic rate constants. Kinetic analysis revealed the rate-limiting step of inactivation of the PLP-dependent enzyme BioA by dihydro-(1,4)-pyridone 1. This knowledge was subsequently applied to rationally design a second-generation inhibitor scaffold with a nearly optimal maximum inactivation rate (0.48 min-1).

Original languageEnglish (US)
Pages (from-to)7132-7135
Number of pages4
JournalJournal of the American Chemical Society
Issue number21
StatePublished - May 31 2017

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health (AI091790 to C.C.A. and GM118030 to J.D.L.). C.E. thanks the NIH for a Chemistry−Biology Interface Predoctoral Traineeship (GM08700). We thank Melanie Rogers and Brent Rivard for assistance with the transient kinetic experiments and Kathleen Wang for assistance with derivations. We thank the reviewer for rigorous evaluation of the kinetic inactivation equations and valuable suggestions for their presentation.

Publisher Copyright:
© 2017 American Chemical Society.


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