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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 p K  a  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 p K  a  values of attached functional groups by additional substituents at the parent scaffold is rendered prominent.

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