Fragment Binding to Kinase Hinge: If Charge Distribution and Local pKa Shifts Mislead Popular Bioisosterism Concepts

Angew Chem Int Ed Engl. 2021 Jan 4;60(1):252-258. doi: 10.1002/anie.202011295. Epub 2020 Oct 29.


Medicinal-chemistry optimization follows strategies replacing functional groups and attaching larger substituents at a promising lead scaffold. Well-established bioisosterism rules are considered, however, it is difficult to estimate whether the introduced modifications really match the required properties at a binding site. The electron density distribution and pKa values are modulated influencing protonation states and bioavailability. Considering the adjacent H-bond donor/acceptor pattern of the hinge binding motif in a kinase, we studied by crystallography a set of fragments to map the required interaction pattern. Unexpectedly, benzoic acid and benzamidine, decorated with the correct substituents, are totally bioisosteric just as carboxamide and phenolic OH. A mono-dentate pyridine nitrogen out-performs bi-dentate functionalities. The importance of correctly designing pKa values of attached functional groups by additional substituents at the parent scaffold is rendered prominent.

Keywords: bioisosterism; drug design; fragments; pKa shift; protein kinase A.