Structural basis for selective PDE 3 inhibition: a docking study

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) catalyse the hydrolysis of the second messengers adenosine-3',5'-cyclic phosphate cAMP and cGMP. At least 11 different PDE types have been described: each of these groups a number of subtypes and splice variants. The PDE types differ in their amino acid sequence, substrate specificity, inhibitor sensitivity and in their organ, tissue and subcellular distribution. The recently solved X-ray structure of PDE4B as well as the results of site-directed mutagenesis experiments on PDE3A, prompted us to further investigate into the molecular mechanism that leads to effective PDE3 inhibition, as a prosecution of our previous studies on characterisation of the catalytic site of PDE family enzymes. On the basis of the experimental data available, a theoretical model of the catalytic site of PDE3A employing homology-modelling techniques was built. On this model thorough docking studies with potent and selective PDE3 inhibitors were performed. The derived inhibition model individuated structural requirements for potent PDE3 inhibition and can now be exploited for rational drug design purposes.