Covalent inhibition is an efficient molecular mechanism for inhibiting enzymes or modulating the function of
proteins and is found in the action of many drugs and biologically active natural products. However, it is has been less
appreciated that the formation of covalent bonds can be reversible or irreversible. This review focuses on biologically
active compounds that are Michael acceptors and how the reversible nature of the Michael addition reaction influences
biological activity and how this can be exploited in designing prodrugs.
Keywords: Covalent inhibition, Michael addition, natural products, prodrug, reversible, polypharmacology, CNS drugs, 3-aminopropanamides, non-covalent, β-unsaturated
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