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Automated computational screening of the thiol reactivity of substituted alkenes

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Abstract

Electrophilic olefins can react with the S–H moiety of cysteine side chains. The formation of a covalent adduct through this mechanism can result in the inhibition of an enzyme. The reactivity of an olefin towards cysteine depends on its functional groups. In this study, 325 reactions of thiol-Michael-type additions to olefins were modeled using density functional theory. All combinations of ethenes with hydrogen, methyl ester, amide, and cyano substituents were included. An automated workflow was developed to perform the construction, conformation search, minimization, and calculation of molecular properties for the reactant, carbanion intermediate, and thioether products for a model reaction of the addition of methanethiol to the electrophile. Known cysteine-reactive electrophiles present in the database were predicted to react exergonically with methanethiol through a carbanion with a stability in the 30–40 kcal mol−1 range. 13 other compounds in our database that are also present in the PubChem database have similar properties. Natural bond orbital parameters were computed and regression analysis was used to determine the relationship between properties of the olefin electronic structure and the product and intermediate stability. The stability of the intermediates is very sensitive to electronic effects on the carbon where the anionic charge is centered. The stability of the products is more sensitive to steric factors.

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Acknowledgments

We thank NSERC of Canada for funding through a Discovery Grant (Application No. 418505-2012) and an Undergraduate Student Research Award for JMS. JMS thanks the Dean of Science of Memorial University for a travel grant. Computational resources were provided by the Compute Canada Consortium (CCI: djk-615-ac). We thank Archita Adluri for proofreading the manuscript. We thank the reviewers for meticulous examination of the manuscript.

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  1. Department of Chemistry, Memorial University of Newfoundland, St. John’s, NL, A1B 3X7, Canada

    Jennifer M. Smith & Christopher N. Rowley

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  1. Jennifer M. Smith
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  2. Christopher N. Rowley
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Correspondence to Christopher N. Rowley.

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Smith, J.M., Rowley, C.N. Automated computational screening of the thiol reactivity of substituted alkenes. J Comput Aided Mol Des 29, 725–735 (2015). https://doi.org/10.1007/s10822-015-9857-0

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