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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)

  1. Kinetic and structural studies of phosphodiesterase-8A and implication on the inhibitor selectivity. Wang H, Yan Z, Yang S, Cai J, Robinson H, Ke H. Biochemistry 47 12760-12768 (2008)
  2. Identification of amino acid residues responsible for the selectivity of tadalafil binding to two closely related phosphodiesterases, PDE5 and PDE6. Cahill KB, Quade JH, Carleton KL, Cote RH. J Biol Chem 287 41406-41416 (2012)
  3. Direct allosteric regulation between the GAF domain and catalytic domain of photoreceptor phosphodiesterase PDE6. Zhang XJ, Cahill KB, Elfenbein A, Arshavsky VY, Cote RH. J Biol Chem 283 29699-29705 (2008)
  4. Biological and structural characterization of Trypanosoma cruzi phosphodiesterase C and Implications for design of parasite selective inhibitors. Wang H, Kunz S, Chen G, Seebeck T, Wan Y, Robinson H, Martinelli S, Ke H. J Biol Chem 287 11788-11797 (2012)
  5. Distinct allostery induced in the cyclic GMP-binding, cyclic GMP-specific phosphodiesterase (PDE5) by cyclic GMP, sildenafil, and metal ions. Biswas KH, Visweswariah SS. J Biol Chem 286 8545-8554 (2011)
  6. An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies. Chen G, Wang H, Robinson H, Cai J, Wan Y, Ke H. Biochem Pharmacol 75 1717-1728 (2008)
  7. Investigation of PDE5/PDE6 and PDE5/PDE11 selective potent tadalafil-like PDE5 inhibitors using combination of molecular modeling approaches, molecular fingerprint-based virtual screening protocols and structure-based pharmacophore development. Kayık G, Tüzün NŞ, Durdagi S. J Enzyme Inhib Med Chem 32 311-330 (2017)
  8. Identification of New Targets and the Virtual Screening of Lignans against Alzheimer's Disease. Dos Santos Maia M, Rodrigues GCS, de Sousa NF, Scotti MT, Scotti L, Mendonça-Junior FJB. Oxid Med Cell Longev 2020 3098673 (2020)
  9. Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor. Huang M, Shao Y, Hou J, Cui W, Liang B, Huang Y, Li Z, Wu Y, Zhu X, Liu P, Wan Y, Ke H, Luo HB. Mol Pharmacol 88 836-845 (2015)
  10. Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure. Shang NN, Shao YX, Cai YH, Guan M, Huang M, Cui W, He L, Yu YJ, Huang L, Li Z, Bu XZ, Ke H, Luo HB. Biochem Pharmacol 89 86-98 (2014)
  11. Insight into binding of phosphodiesterase-9A selective inhibitors by crystal structures and mutagenesis. Wang H, Luo X, Ye M, Hou J, Robinson H, Ke H. J Med Chem 53 1726-1731 (2010)
  12. Interactions between cyclic nucleotide phosphodiesterase 11 catalytic site and substrates or tadalafil and role of a critical Gln-869 hydrogen bond. Weeks JL, Corbin JD, Francis SH. J Pharmacol Exp Ther 331 133-141 (2009)
  13. Repeated and chronic administration of Vardenafil or Sildenafil differentially affects emotional and socio-sexual behavior in mice. Dadomo H, Parmigiani S, Nicolini Y, Freschini S, Gioiosa L, Patrelli TS, Palanza P, Volpi R. Behav Brain Res 253 103-112 (2013)
  14. Charting the interactome of PDE3A in human cells using an IBMX based chemical proteomics approach. Corradini E, Klaasse G, Leurs U, Heck AJ, Martin NI, Scholten A. Mol Biosyst 11 2786-2797 (2015)
  15. Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5. Chau Y, Li FS, Levsh O, Weng JK. PLoS One 14 e0222803 (2019)
  16. A synthetic mimic of phosphodiesterase type 5 based on corona phase molecular recognition of single-walled carbon nanotubes. Dong J, Lee MA, Rajan AG, Rahaman I, Sun JH, Park M, Salem DP, Strano MS. Proc Natl Acad Sci U S A 117 26616-26625 (2020)
  17. Histone deacetylase inhibitors synergize with sildenafil to suppress purine metabolism and proliferation in pulmonary hypertension. Zhang H, D'Alessandro A, Li M, Reisz JA, Riddle S, Muralidhar A, Bull T, Zhao L, Gerasimovskaya E, Stenmark KR. Vascul Pharmacol 149 107157 (2023)
  18. Phosphodiesterase Type 5 Inhibitors Greatly Affect Physicochemical Properties of Model Lipid Membranes. Zakharova AA, Efimova SS, Ostroumova OS. Membranes (Basel) 11 893 (2021)
  19. Coupling of conformational dynamics and inhibitor binding in the phosphodiesterase-5 family. Tripathi S, Cote RH, Vashisth H. Protein Sci 32 e4720 (2023)
  20. Molecular Dynamics Simulation of the Complex of PDE5 and Evodiamine. Kobayashi A, Nakajima M, Noguchi Y, Morikawa R, Matsuo Y, Takasu M. Life (Basel) 13 578 (2023)


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