An Updated Topographical Model for Phosphodiesterase 4 (PDE4) Catalytic Site

Preclinical and clinical studies on cyclic nucleotide phosphodiesterases 4 (PDE4) inhibitors showed that these agents might be employed in the treatment of allergic diseases, in particular asthma. Unfortunately, many of these compounds such as rolipram, which belongs to the so-called “first generation”, showed undesirable side effects such as nausea and emesis. Efforts to eliminate these adverse side effects prompted the synthesis of a “second generation” of PDE4 inhibitors, with improved selectivity towards the enzyme catalytic site. So as to refine the pharmacophoric models of the catalytic site previously described in literature and better define the structural requirements which are essential for potent and selective PDE4 inhibition, we undertook the present computational study. DISCO approach was applied to generate an optimal alignment for a set of structurally diverse selective inhibitors 1–18 chosen from literature. The resulting superimposition of common pharmacophoric elements was refined by evaluating molecular field properties. A rational pharmacophoric model of the enzyme active site was thus derived and tested for its ability in predicting the degree of potency for a novel ligand. The comparison of the pharmacophoric areas common to cAMP, the natural substrate of the enzyme, and the most selective inhibitors was performed so as to better understand the binding mode of PDE4 selective inhibitors in the catalytic site.