Identification of PDE4B Over 4D subtype-selective inhibitors revealing an unprecedented binding mode

A PDE4B over 4D-selective inhibitor programme was initiated to capitalise on the recently discovered predominance of the PDE4B subtype in inflammatory cell regulation. The SAR of a tetrahydrobenzothiophene (THBT) series did not agree with either of two proposed docking modes in the 4B binding site. A subsequent X-ray co-crystal structure determination revealed that the THBT ligand displaces the Gln-443 residue, invariably ligand-anchoring in previous PDE4 co-crystal structures, and even shifts helix-15 by 1–2 Å. For the first time, several residues of the C-terminus previously proposed to be involved in subtype selectivity are resolved and three of them extend into the ligand binding site potentially allowing for selective drug design.

A new co-crystal PDE4B structure pushes the usual ligand anchor Gln-443 out of the active site. Unprecedented resolution of C-terminal residues gives access to PDE4B/4D ligand design.Figure optionsDownload as PowerPoint slide