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Fragment Binding to Kinase Hinge: If Charge Distribution and Local p K a Shifts Mislead Popular Bioisosterism Concepts
Author(s) -
Oebbeke Matthias,
Siefker Christof,
Wagner Björn,
Heine Andreas,
Klebe Gerhard
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202011295
Subject(s) - protonation , chemistry , pyridine , benzoic acid , stereochemistry , combinatorial chemistry , crystallography , medicinal chemistry , organic chemistry , ion
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.