A fragment library of electrophilic small heterocycles was characterized through cysteine-reactivity
and aqueous stability tests that suggested their potential as covalent warheads. The
analysis of theoretical and experimental descriptors revealed correlations between
the electronic properties of the heterocyclic cores and their reactivity against GSH
that are helpful in identifying suitable fragments for cysteines with specific nucleophilicity.
The most important advantage of these fragments is that they show only minimal structural
differences from non-electrophilic counterparts. Therefore, they could be used effectively
in the design of targeted covalent inhibitors with minimal influence on key non-covalent
interactions.
