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

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Despite close structural similarity, vardenafil (Levitra®) is 32-fold more potent than sildenafil (Viagra®) 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 Tyr612, a catalytic site AA, via (1) a hydrogen bond with a water molecule and (2) hydrophobic bonds. For mutant PDE5Y612F, which ablates hydrogen-bonding potential, vardenafil or sildenafil inhibition was strengthened (2.2- or 3.0-fold, respectively), implying that the Tyr612 hydroxyl is a negative determinant for these inhibitors. For mutant PDE5Y612A, 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 Tyr612 are stronger for vardenafil than for sildenafil.

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