Tyrosine-612 in PDE5 contributes to higher affinity for vardenafil over sildenafil

Despite close structural similarity, vardenafil (Levitra(R)) is 32-fold more potent than sildenafil (Viagra(R)) to inhibit cGMP-binding cGMP-specific PDE (PDE5); this is due to differences between their heterocyclic rings. In co-crystals with PDE5, one of the rings of vardenafil or sildenafil interacts with Tyr(612), a catalytic site AA, via ( 1) a hydrogen bond with a water molecule and ( 2) hydrophobic bonds. For mutant PDE5(Y612F), which ablates hydrogen-bonding potential, vardenafil or sildenafil inhibition was strengthened (2.2- or 3.0-fold, respectively), implying that the Tyr(612) hydroxyl is a negative determinant for these inhibitors. For mutant PDE5(Y612A), which ablates both hydrogen bonding and hydrophobic-bonding potential, vardenafil inhibition was weakened much more than sildenafil inhibition (122- and 26-fold, respectively), suggesting that hydrophobic bonds involving Tyr(612) are stronger for vardenafil than for sildenafil.