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 1-2A. 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.
Kranz
Michael
M
Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, England, UK. michael.j.kranz@gsk.com
Wall
Michael
M
Evans
Brian
B
Miah
Afjal
A
Ballantine
Stuart
S
Delves
Chris
C
Dombroski
Brian
B
Gross
Jeffrey
J
Schneck
Jessica
J
Villa
James P
JP
Neu
Margarete
M
Somers
Don O
DO
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D058988:Phosphodiesterase 4 Inhibitors; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000378:metabolism*
D058988:Phosphodiesterase 4 Inhibitors; D013876:Thiophenes; C121030:tetrahydrothiophene; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human