Site of reactivity models predict molecular reactivity of diverse chemicals with glutathione

Chemical Research in Toxicology
Tyler B HughesS Joshua Swamidass

Abstract

Drug toxicity is often caused by electrophilic reactive metabolites that covalently bind to proteins. Consequently, the quantitative strength of a molecule's reactivity with glutathione (GSH) is a frequently used indicator of its toxicity. Through cysteine, GSH (and proteins) scavenges reactive molecules to form conjugates in the body. GSH conjugates to specific atoms in reactive molecules: their sites of reactivity. The value of knowing a molecule's sites of reactivity is unexplored in the literature. This study tests the value of site of reactivity data that identifies the atoms within 1213 reactive molecules that conjugate to GSH and builds models to predict molecular reactivity with glutathione. An algorithm originally written to model sites of cytochrome P450 metabolism (called XenoSite) finds clear patterns in molecular structure that identify sites of reactivity within reactive molecules with 90.8% accuracy and separate reactive and unreactive molecules with 80.6% accuracy. Furthermore, the model output strongly correlates with quantitative GSH reactivity data in chemically diverse, external data sets. Site of reactivity data is nearly unstudied in the literature prior to our efforts, yet it contains a strong signal for ...Continue Reading

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Citations

Jan 6, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jarosław SławińskiAnna Kawiak
Sep 10, 2016·ACS Central Science·Tyler B HughesS Joshua Swamidass
Oct 18, 2016·Journal of Chemical Information and Modeling·Peter SadowskiPierre Baldi
Jan 19, 2017·Chemical Research in Toxicology·Tyler B Hughes, S Joshua Swamidass
Mar 4, 2017·Chemical Research in Toxicology·Na Le DangS Joshua Swamidass
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Feb 6, 2021·Environmental Science and Pollution Research International·Vinod Kumar Nathan, Mary Esther Rani
Jan 27, 2021·Chemical Research in Toxicology·Tyler B HughesS Joshua Swamidass
Feb 11, 2020·Journal of Chemical Information and Modeling·Na Le DangS Joshua Swamidass
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Sep 4, 2020·Journal of Chemical Information and Modeling·Tyler B HughesS Joshua Swamidass
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Jul 12, 2019·Chemical Reviews·Xin YangShengyong Yang
Jul 16, 2019·Chemical Research in Toxicology·Matthew K MatlockS Joshua Swamidass
Oct 22, 2020·The Journal of Physical Chemistry. a·Kathryn SarulloS Joshua Swamidass
Jul 11, 2018·Journal of Chemical Information and Modeling·Matthew K MatlockS Joshua Swamidass
Jun 28, 2019·Journal of Chemical Information and Modeling·Ferruccio PalazzesiChristofer S Tautermann
May 11, 2016·ACS Central Science·Amit S Kalgutkar
May 11, 2016·ACS Central Science·Tyler B HughesS Joshua Swamidass
Jan 23, 2018·Chemical Research in Toxicology·Na Le DangS Joshua Swamidass
Feb 3, 2018·ACS Central Science·Matthew K MatlockS Joshua Swamidass

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