MEDI 265 |
| Phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP or cGMP which regulate a variety of cellular processes and are prime targets for drug development. We have shown that an invariant glutamine functions as the key specificity determinant by a “glutamine switch” mechanism for recognizing the purine moiety in cAMP or cGMP. We have found a common scheme of inhibitor binding to the PDEs: (i) A hydrophobic clamp formed by highly conserved hydrophobic residues that sandwich the inhibitor in the active site; (ii) hydrogen bonding to an invariant glutamine that controls the orientation of inhibitor binding. A scaffold can be readily identified for any given inhibitor based on the formation of these two types of conserved interactions. We describe a scaffold-based drug design approach applied on the discovery of several new classes of PDE4 inhibitors. This method starts with low affinity screening of a low molecular weight compound library followed by high throughput co-crystallography of the screening hits to select compounds that exhibit a dominant binding mode and have appropriate sites for substitution. These scaffolds compounds serve as the starting point for lead development. We report two lead series with different profiles of PDE4 selectivity discovered using our scaffold-based drug discovery platform, which have been evaluated in preclinical studies. |
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Phosphodiesterase Inhibitors
1:30 PM-5:00 PM, Wednesday, August 22, 2007 BCEC -- 213, Oral
Division of Medicinal Chemistry |