353787-06-1Relevant academic research and scientific papers
Identification of PDE4B Over 4D subtype-selective inhibitors revealing an unprecedented binding mode
Kranz, Michael,Wall, Michael,Evans, Brian,Miah, Afjal,Ballantine, Stuart,Delves, Chris,Dombroski, Brian,Gross, Jeffrey,Schneck, Jessica,Villa, James P.,Neu, Margarete,Somers, Don O.
experimental part, p. 5336 - 5341 (2009/10/23)
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 A. 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.
