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Chemical and Computational Methods for the Characterization of Covalent Reactive Groups for the Prospective Design of Irreversible Inhibitors

Flanagan, Mark E., Abramite, Joseph A., Anderson, Dennis P., Aulabaugh, Ann, Dahal, Upendra P., Gilbert, Adam M., Li, Chao, Montgomery, Justin, Oppenheimer, Stacey R., Ryder, Tim, Schuff, Brandon P., Uccello, Daniel P., Walker, Gregory S., Wu, Yan, Brown, Matthew F., Chen, Jinshan M., Hayward, Matthew M., Noe, Mark C., Obach, R. Scott, Philippe, Laurence, Shanmugasundaram, Veerabahu, Shapiro, Michael J., Starr, Jeremy, Stroh, Justin, Che, Ye·2014·Journal of Medicinal Chemistry

DOI 10.1021/jm501412a

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Abstract

Interest in drugs that covalently modify their target is driven by the desire for enhanced efficacy that can result from the silencing of enzymatic activity until protein resynthesis can occur, along with the potential for increased selectivity by targeting uniquely positioned nucleophilic residues in the protein. However, covalent approaches carry additional risk for toxicities or hypersensitivity reactions that can result from covalent modification of unintended targets. Here we describe methods for measuring the reactivity of covalent reactive groups (CRGs) with a biologically relevant nucleophile, glutathione (GSH), along with kinetic data for a broad array of electrophiles. We also describe a computational method for predicting electrophilic reactivity, which taken together can be applied to the prospective design of thiol-reactive covalent inhibitors.

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Authors: Flanagan, M. E., Abramite, J. A., Anderson, D. P., Aulabaugh, A., Dahal, U. P., Gilbert, A. M., Li, C., Montgomery, J., Oppenheimer, S. R., Ryder, T., Schuff, B. P., Uccello, D. P., Walker, G. S., Wu, Y., Brown, M. F., Chen, J. M., Hayward, M. M., Noe, M. C., Obach, R. S., Philippe, L., Shanmugasundaram, V., Shapiro, M. J., Starr, J., Stroh, J., & Che, Y.
Venue: Journal of Medicinal Chemistry
Publisher: American Chemical Society (ACS)
Published: 2014-11-26
Volume: 57
Issue: 23
Pages: 10072-10079
ISSN: 0022-2623 (ISSN-L)
1520-4804
DOI: 10.1021/jm501412a
OpenAlex: W2322586343
Cited by: 320
References: 35
FWCI: 9.11
Type: journal article
Language: en
Open access: closed

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Chemical and Computational Methods for the Characterization of Covalent Reactive Groups for the Prospective Design of Irreversible Inhibitors

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