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Title: Conformational Variations of Both Phosphodiesterase-5 and Inhibitors Provide the Structural Basis for the Physiological Effects of Vardenafil and Sildenafil

Abstract

Vardenafil has higher affinity to phosphodiesterase-5 (PDE5) than sildenafil and lower administered dosage for the treatment of erectile dysfunction. However, the molecular basis for these differences is puzzling because two drugs have similar chemical structures. Reported here is a crystal structure of the fully active and nonmutated PDE5A1 catalytic domain in complex with vardenafil. The structure shows that the conformation of the H-loop in the PDE5A1-vardenafil complex is different from those of any known structures of the unliganded PDE5 and its complexes with the inhibitors. In addition, the molecular configuration of vardenafil differs from that of sildenafil when bound to PDE5. It is noteworthy that the binding of vardenafil causes loss of the divalent metal ions that have been observed in all the previously published PDE structures. The conformational variation of both PDE5 and the inhibitors provides structural insight into the different potencies of the drugs.

Authors:
; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
980079
Report Number(s):
BNL-92997-2010-JA
Journal ID: ISSN 0026-895X; MOPMA3; TRN: US201015%%1464
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Molecular Pharmacology; Journal Volume: 73; Journal Issue: 1
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; 59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; AFFINITY; COMPLEXES; CONFIGURATION; CRYSTAL STRUCTURE; DRUGS; IONS; METALS; VARIATIONS; national synchrotron light source

Citation Formats

Wang, H., Ye, M, Robinson, H, Fransis, S, and Ke, H. Conformational Variations of Both Phosphodiesterase-5 and Inhibitors Provide the Structural Basis for the Physiological Effects of Vardenafil and Sildenafil. United States: N. p., 2007. Web. doi:10.1124/mol.107.040212.
Wang, H., Ye, M, Robinson, H, Fransis, S, & Ke, H. Conformational Variations of Both Phosphodiesterase-5 and Inhibitors Provide the Structural Basis for the Physiological Effects of Vardenafil and Sildenafil. United States. doi:10.1124/mol.107.040212.
Wang, H., Ye, M, Robinson, H, Fransis, S, and Ke, H. Mon . "Conformational Variations of Both Phosphodiesterase-5 and Inhibitors Provide the Structural Basis for the Physiological Effects of Vardenafil and Sildenafil". United States. doi:10.1124/mol.107.040212.
@article{osti_980079,
title = {Conformational Variations of Both Phosphodiesterase-5 and Inhibitors Provide the Structural Basis for the Physiological Effects of Vardenafil and Sildenafil},
author = {Wang, H. and Ye, M and Robinson, H and Fransis, S and Ke, H},
abstractNote = {Vardenafil has higher affinity to phosphodiesterase-5 (PDE5) than sildenafil and lower administered dosage for the treatment of erectile dysfunction. However, the molecular basis for these differences is puzzling because two drugs have similar chemical structures. Reported here is a crystal structure of the fully active and nonmutated PDE5A1 catalytic domain in complex with vardenafil. The structure shows that the conformation of the H-loop in the PDE5A1-vardenafil complex is different from those of any known structures of the unliganded PDE5 and its complexes with the inhibitors. In addition, the molecular configuration of vardenafil differs from that of sildenafil when bound to PDE5. It is noteworthy that the binding of vardenafil causes loss of the divalent metal ions that have been observed in all the previously published PDE structures. The conformational variation of both PDE5 and the inhibitors provides structural insight into the different potencies of the drugs.},
doi = {10.1124/mol.107.040212},
journal = {Molecular Pharmacology},
number = 1,
volume = 73,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}