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• Binding Mode

  The electron density map corresponding to zanubrutinib and Cys481 showed covalent linkage with Cys481. Zanubrutinib forms three critical hydrogen bonds with hinge residues Glu475 and  Met477. Compared with the co-crystal structure of ibrutinib with BTK, there is an additional hydrogen bond between the backbone carbonyl oxygen of Met477 and the 4-NH. The terminal phenyl group engages in a T-shape π–π stacking with Phe540, and the pyrazolyl nitrogen interacts with Lys430 via a water bridge. The warhead carbonyl also interacts indirectly with the amide NH of Asn484 via two water molecules. Both zanubrutinib and ibrutinib have a piperidinyl linker; however, they adopt two different binding modes in complex with BTK. In addition, a single crystal X-ray structure of zanubrutinib showed a classic intramolecular H-bond between carboxamide oxygen and the 4-NH, which confirmed the bioisosteric mimicry of the aminopyrimidine ring.;

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