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

International Journal of Impotence Research volume 18, pages 251–257 (2006)Cite this article

A Corrigendum to this article was published on 04 July 2006

Abstract

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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Abbreviations

PDE:

3′,5′-cyclic nucleotide phosphodiesterase

PDE5A:

cGMP-binding cGMP-specific PDE

KPEM:

10 mM potassium phosphate

pH 6.8:

1 mM EDTA, and 25 mM β-mercaptoethanol

IBMX:

3-isobutyl-1-methylxanthine

DTT:

DL-dithiothreitol

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Authors and Affiliations

  1. Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA

    J Corbin, S Francis & R Zoraghi

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  1. J Corbin
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  2. S Francis
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Correspondence to J Corbin.

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Corbin, J., Francis, S. & Zoraghi, R. Tyrosine-612 in PDE5 contributes to higher affinity for vardenafil over sildenafil. Int J Impot Res 18, 251–257 (2006). https://doi.org/10.1038/sj.ijir.3901411

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