872211 JBXXXX10.1177/2472555219872211SLAS DISCOVERY: Advancing Life Sciences R&DWalsh research-article2019 Perspective SLAS Discovery © 2019 Society for Laboratory Response to the Article “Enzyme–Inhibitor Automation and Screening https://doi.org/10.1177/2472555219872211 DOI: 10.1177/2472555219872211 Interactions and a Simple, Rapid Method journals.sagepub.com/home/jbx for Determining Inhibition Modality” Ryan Walsh Having come across this article, I was quite disappointed quickly and easily test this approach with their own data in its one-sided biased endorsement of classical inhibition and evaluate the fit against the classical models using a models. freely available Excel template. Therefore, it is a disservice Whereas it may be inconceivable to many biochemists to the research community for the authors to recommend practicing in the field today that there is controversy sur- constraining mechanistic studies to classical inhibition rounding the classical models of enzyme inhibition, one equations with clear mathematical limitations based on only needs to look at the propagation of subsequent inhibi- mechanistic models the authors concede are not valid. tion models over the years to realize that the classical way Declaration of Conflicting Interests of modeling segregates interactions into very strict pre- defined limitations. For example, traditional competitive The author declared no potential conflicts of interest with respect inhibitors only decrease substrate affinity by linearly to the research, authorship, and/or publication of this article. increasing the value of the K with increasing inhibitor concentration. However, a mathematical model does not Funding indicate mechanism; rather, it provides support for a hypoth- The author received no financial support for the research, author- esis, which is why you may have allosteric effects that pres- ship, and/or publication of this article. ent as competitive, as outlined by the authors. Given that these equations do not really define specific interactions, ORCID iD there should be no point in advocating their use if there is a Ryan Walsh https://orcid.org/0000-0002-3794-4721 single equation that can model the data as well as or, in most cases, better than they can. The omission of this point from References the article greatly reduces the overall usefulness of a review. 1. Buker, S. M.; Boriack-Sjodin, P. A.; Copeland, R. A. By recognizing that the apparent inhibition term in the Enzyme–Inhibitor Interactions and a Simple, Rapid Method classical inhibition equations is an inversion of the inhibitor for Determining Inhibition Modality. SLAS Discov. 2019, 24, binding isotherm (eq 1), one can directly relate changes in 515–522. enzymatic activity to the fraction of the enzymatic popula- 2. Walsh, R. 2012. Alternative Perspectives of Enzyme Kinetic tion bound. Consequently, changes in enzymatic activity Modeling. In Medicinal Chemistry and Drug Design, Ekinci, can be described through observation rather than strictly D., Ed.; InTech: Rijeka, Croatia, 2012, pp 357–372. 3. Walsh, R.; Martin, E.; Darvesh, S. A Versatile Equation to defined limits imposed by the classical equations (eq 2). Describe Reversible Enzyme Inhibition and Activation Kinetics: Modeling Beta-Galactosidase and Butyrylcholinesterase. I I   (1) 11 + =− Biochim. Biophys. Acta. 2007, 1770, 733–746. K IK +  ii 4. Walsh, R. Comparing Enzyme Activity Modifier Equations through the Development of Global Data Fitting Templates in Excel. PeerJ 2018, 6, e6082. 5. Walsh, R. A Reanalysis of Protein Tyrosine Phosphatases S X   (2) v = VV − Δ Inhibitory Studies Using the Unnatural Substrate Analogue X XK +   p-Nitrophenyl Phosphate. Anal. Biochem. 2019, 572, 58–62.  SK +− ΔK XK +  INRS, Laval, QC, Canada This equation has been tested against the classical equations Received July 8, 2019, and in revised form July 28, 2019. Accepted for publication Aug 5, 2019. with real data and has been found to allow for an equivalent 3–5 or improved fit in all cases. The flexibility of this Corresponding Author: approach also allows the equation to be used to describe Ryan Walsh, INRS, 531 Boul Des Prairies, Laval, QC H7V 1B7, Canada. Email: Ryan.Walsh@iaf.inrs.ca activators in addition to inhibitors. Any researchers can also
SLAS Discovery – SAGE
Published: Jan 1, 2019
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