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Conformational variations of both phosphodiesterase-5 and inhibitors provide the structural basis for the physiological effects of vardenafil and sildenafil.

Wang H, Ye M, Robinson H, Francis SH, Ke H
Mol Pharmacol 73 104-10 (2008)
Cited: 27 times
EuropePMC logo PMID: 17959709

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.

Articles - 3b2r mentioned but not cited (4)

  1. Conformational variations of both phosphodiesterase-5 and inhibitors provide the structural basis for the physiological effects of vardenafil and sildenafil. Wang H, Ye M, Robinson H, Francis SH, Ke H. Mol Pharmacol 73 104-110 (2008)
  2. Identification of a Novel 1,2,3,4-Tetrahydrobenzo[b][1,6]naphthyridine Analogue as a Potent Phosphodiesterase 5 Inhibitor with Improved Aqueous Solubility for the Treatment of Alzheimer's Disease. Fiorito J, Vendome J, Saeed F, Staniszewski A, Zhang H, Yan S, Deng SX, Arancio O, Landry DW. J Med Chem 60 8858-8875 (2017)
  3. Identification of a PDE4-Specific Pocket for the Design of Selective Inhibitors. Feng X, Wang H, Ye M, Xu XT, Xu Y, Yang W, Zhang HT, Song G, Ke H. Biochemistry 57 4518-4525 (2018)
  4. Geodemographic Patterns of Meat Expenditure in Great Britain. James WHM, Lomax N, Birkin M, Collins LM. Appl Spat Anal Policy 14 563-590 (2021)


Reviews citing this publication (3)

  1. Advances in targeting cyclic nucleotide phosphodiesterases. Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello VC. Nat Rev Drug Discov 13 290-314 (2014)
  2. Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Francis SH, Blount MA, Corbin JD. Physiol Rev 91 651-690 (2011)
  3. Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair. Knott EP, Assi M, Rao SN, Ghosh M, Pearse DD. Int J Mol Sci 18 E696 (2017)

Articles citing this publication (20)



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