Covalent Binding of the Boronic Acid-Based Inhibitor GSK4394835A to Phosphodiesterase 3B, a Drug Target for Cardiovascular Disease

Boronic acid inhibitors
often undergo nucleophilic addition upon
binding to an enzyme due to the electrophilicity of the boron atom.
A new class of boronic acid inhibitors of human phosphodiesterase
3B (PDE3B) has recently been disclosed, along with the 2.7 Å-resolution
crystal structure of PDE3B complexed with inhibitor GSK4394835A [Rowley
et al. (2024) Discovery and SAR study of boronic acid-based selective
PDE3B inhibitors from a novel DNA-encoded library. J. Med.
Chem. 67, 2049–2065]. The crystal structure shows
the binding of an intact, unreacted boronic acid, but discrepancies
were evident in refinement statistics. Accordingly, we redetermined
the structure using structure factor amplitudes deposited in the Protein
Data Bank (accession code 8SYC), showing that the boronic acid moiety
of GSK4394835A undergoes nucleophilic attack by H737 to form a tetrahedral
boronate anion. We refined the structure to convergence with excellent
refinement statistics, concluding that GSK4394835A is a reversible
covalent inhibitor of PDE3B.