jo6b02188_si_001.pdf (6.59 MB)
Kinetics and Thermodynamics of Reversible Thiol Additions to Mono- and Diactivated Michael Acceptors: Implications for the Design of Drugs That Bind Covalently to Cysteines
journal contribution
posted on 2016-11-08, 20:53 authored by Elizabeth H. Krenske, Russell
C. Petter, K. N. HoukAdditions
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.