Fragment Binding to Kinase Hinge: If Charge Distribution and Local pKa Shifts Mislead Popular Bioisosterism Concepts |
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Authors: | Matthias Oebbeke,Christof Siefker,Bj rn Wagner,Andreas Heine,Gerhard Klebe |
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Affiliation: | Matthias Oebbeke,Christof Siefker,Björn Wagner,Andreas Heine,Gerhard Klebe |
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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 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. |
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Keywords: | bioisosterism drug design fragments pKa shift protein kinase A |
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