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

Correspondence: Professor J Corbin, Molecular Physiology and Biophysics, Vanderbilt University, 21st & Garland, Nashville, TN 37232-0615, USA. E-mail: jackie.corbin@vanderbilt.edu

Received 8 June 2005; Revised 20 September 2005; Accepted 20 September 2005; Published online 10 November 2005.

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 PDE5_Y612F, 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 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 Tyr⁶¹² are stronger for vardenafil than for sildenafil.