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

ABSTRACT: 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 pK_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

SUBMITTER: Oebbeke M 

PROVIDER: S-EPMC7821265 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature