LAUSR

The commentary by Dr. Walsh offers a depth of mathematical precision that is to be applauded. We congratulate him on this alternative mathematical treatment of enzyme– inhibitor interactions. At the same time, there is value in recognizing that all experimental science is reductionist, and this is especially true in fields like medicine and drug discovery, where researchers seek to understand the overwhelming complexity of human biology through simple models that, while admittedly incomplete, provide a cogent and systematic approach to tackling some devastatingly critical societal issues. The classical model of enzyme–inhibitor interactions has pedagogic value and has served the medical and drug discovery communities exceedingly well for more than a century. Dr. Walsh correctly points out that the classic definitions of competitive, noncompetitive, and uncompetitive inhibition are simplistic and limiting. Nevertheless, they are quite useful in framing the researcher’s understanding of the potential for competitive displacement of inhibitors by substrate molecules within the intracellular milieu—an important issue in the translation of in vitro enzyme–inhibitor affinity to cellular and in vivo pharmacodynamics. We hope that we have made clear in our published works that these labels merely reflect important points along a continuum of enzyme–inhibitor–substrate interactions. The overarching point that we wished to communicate in our paper is that terms like competitive, noncompetitive, and uncompetitive inhibition refer to thermodynamic properties of inhibitors with respect to their reciprocal impact on the association of the target enzyme with substrate and, importantly, do not convey any specificity with respect to binding site location vis-à-vis the orthosteric, active site of the enzyme. Hence, our paper was intended mainly to caution the drug discovery community against inappropriately conflating thermodynamic properties with binding site localization; this is especially important and timely, given the current interest in allosteric inhibition as a basis for therapeutic intervention. In this regard, we believe that the inhibitor modality descriptions that we provided not only are consistent with wellestablished norms but also served the stated pedagogic goals of our article. 875106 JBXXXX10.1177/2472555219875106SLAS DISCOVERY: Advancing Life Sciences R&DCopeland research-article2019