Crystal structures reveal a second binding mode of thiophene inhibitors of PDE4 — ASN Events
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Crystal structures reveal a second binding mode of thiophene inhibitors of PDE4 (#208)

Susanne C. Feil 1 , Nancy C. Hancock 1 , Jacob L. Nankervis 2 , Diana S. Neale 2 , Zhaohua Zheng 2 , David T. Manallack 2 , Ian G. Jennings 2 , Hooi-LIng Ng 1 , Craig J. Morton 1 , Jessica K. Holien 1 , Pat W.M. Ho 3 , T. John Martin 3 , Philip E. Thompson 2 , Michael W. Parker 1 4
  1. Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
  2. Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
  3. Bone Cell Biology and Disease Unit, St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
  4. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, Parkville, VIC, Australia

Phosphodiesterases (PDEs) are enzymes that regulate the intracellular levels of cAMP and cGMP. The regulation of cAMP and cGMP in cells is essential in many physiological processes such as cardiac and smooth muscle contraction, platelet aggregation, apoptosis, growth control and neurological function. PDEs are categorised into 11 families (PDE1-11). PDE4 specifically hydrolyses cAMP and has four similar subfamily genes PDE4A-D. PDE4D is involved in diseases such as asthma and chronic obstructive pulmonary diseases. A number of PDE4 inhibitors have been identified but their side-effects rendered the inhibitors not suitable for further development. During a study to discover antagonists of the parathyroid hormone receptor we serendipitously discovered a new class of PDE4 inhibitors. We present the crystal structures of six PDE4/inhibitor complexes and their binding modes.