title: Kinetics and Thermodynamics of Reversible Thiol Additions to Mono- and Diactivated Michael Acceptors: Implications for the Design of Drugs That Bind Covalently to Cysteines.
abstract: Additions of cysteine thiols to Michael acceptors underpin the mechanism of action of several covalent drugs (e.g., afatinib, osimertinib, ibrutinib, neratinib, and CC-292). Reversible Michael acceptors have been reported in which an additional electron-withdrawing group was added at the α-carbon of a Michael acceptor. We have performed density functional theory calculations to determine why thiol additions to these Michael acceptors are reversible. The α-EWG group stabilizes the anionic transition state and intermediate of the Michael addition, but less intuitively, it destabilizes the neutral adduct. This makes the reverse reaction (elimination) both faster and more thermodynamically favorable. For thiol addition to be reversible, the Michael acceptor must also contain a suitable substituent on the β-carbon, such as an aryl or branched alkyl group. Computations explain how these structural elements contribute to reversibility and the ability to tune the binding affinities and the residence times of covalent inhibitors.
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Krenske
authors.affiliation: Celgene Avilomics Research , 200 Cambridgepark Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Russell C
authors.initials: RC
authors.lastname: Petter
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.
authors.forename: K N
authors.initials: KN
authors.lastname: Houk
mesh_terms: D001665:Binding Sites; D003545:Cysteine / Q000737:chemistry*; D015195:Drug Design; D007700:Kinetics; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D013438:Sulfhydryl Compounds; D003545:Cysteine