Conformational Variations of Both Phosphodiesterase-5 and Inhibitors Provide the Structural Basis for the Physiological Effects of Vardenafil and Sildenafil

Abstract

Vardenafil has higher affinity to phosphodiesterase-5 (PDE5) than sildenafil and lower administered dosage for the treatment of erectile dysfunction. However, the molecular basis for these differences is puzzling because two drugs have similar chemical structures. Reported here is a crystal structure of the fully active and nonmutated PDE5A1 catalytic domain in complex with vardenafil. The structure shows that the conformation of the H-loop in the PDE5A1-vardenafil complex is different from those of any known structures of the unliganded PDE5 and its complexes with the inhibitors. In addition, the molecular configuration of vardenafil differs from that of sildenafil when bound to PDE5. It is noteworthy that the binding of vardenafil causes loss of the divalent metal ions that have been observed in all the previously published PDE structures. The conformational variation of both PDE5 and the inhibitors provides structural insight into the different potencies of the drugs.Cyclic nucleotide phosphodiesterases (PDEs) are key enzymes controlling cellular concentrations of the second messengers cAMP and cGMP (Mehats

Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor

“…5A), is slightly deeper than that of PDE9. However, two large gating residues of Leu804 and Met816 would allow a small group to penetrate into the pocket, such as an ethoxyl fragment in the PDE5-sildenafil structure (Wang et al, 2008b). This might explain why (S)-C33 has better selectivity than (R)-C33 against PDE5 ( Table 2).…”

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

“…The impact of other conserved amino acids lining the catalytic site is modest (76,406,439,440). The H-loop that adjoins the metal-binding site in the primary sequence of PDEs and begins with an invariant glycine has been implicated in determining interactions with substrates and inhibitors (63,161,163,183,287,400,403). In the x-ray crystallographic structure of the near full-length PDE2, insertion of the H-loop into the catalytic site is suggested to be a critical part of the autoinhibitory mechanism ( Fig.…”

“…In the x-ray crystallographic structure of the near full-length PDE2, insertion of the H-loop into the catalytic site is suggested to be a critical part of the autoinhibitory mechanism ( Fig. 3) (287), and in the PDE5 C domain it assumes multiple conformations dictated largely by the inhibitor that is bound (183,400,403). The full implications of the role of the H-loop in PDE functions are yet to be determined, since its deletion in the isolated C domain of PDE5 causes minimal disruption in function (400).…”

Biological and Structural Characterization of Trypanosoma cruzi Phosphodiesterase C and Implications for Design of Parasite Selective Inhibitors

“…On the other hand, the H-loop at the active site of TcrPDEC favorably compares with that of human PDE4 but not PDE5. Because most human PDE families have an H-loop conformation similar to PDE4 and PDE5 uniquely shows multiple conformations (42,45,46), the H-loop might not be an attractive target for the design of TcrPDEC inhibitors.…”