title: Tyrosine-612 in PDE5 contributes to higher affinity for vardenafil over sildenafil.
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 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.
authors.affiliation: Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. jackie.corbin@vanderbilt.edu
authors.forename: J
authors.initials: J
authors.lastname: Corbin
authors.forename: S
authors.initials: S
authors.lastname: Francis
authors.forename: R
authors.initials: R
authors.lastname: Zoraghi
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000737:chemistry; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D002384:Catalysis; D002460:Cell Line; D006152:Cyclic GMP / Q000737:chemistry / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D009584:Nitrogen / Q000737:chemistry; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011687:Purines; D000068677:Sildenafil Citrate; D013379:Substrate Specificity; D013450:Sulfones / Q000737:chemistry / Q000378:metabolism; D014227:Triazines / Q000737:chemistry / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*; D000069058:Vardenafil Dihydrochloride
chemical_list: D007093:Imidazoles; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014227:Triazines; D014443:Tyrosine; D000069058:Vardenafil Dihydrochloride; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D006152:Cyclic GMP; D009584:Nitrogen; D015056:1-Methyl-3-isobutylxanthine