Fig. 1. Covalent inhibitors in medicinal chemistry and natural products.

(A and B) Three compounds covalently binding to their protein targets. AMG510, a G12C RAS inhibitor [Protein Data Bank (PDB) ID: 6OIM], cyclostreptin binding to His²²⁹ of tubulin (PDB ID: 6QTN), and Bruton’s tyrosine kinase inhibitor zanubrutinib (PDB ID: 6J6M). (C) Common electrophilic warheads and nucleophilic amino acid targets. (D) Synthetic strategies to covalent inhibitors.