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3D-QSAR modeling of Phosphodiesterase-5 inhibitors: evaluation and comparison of the receptor- and ligand-based alignments

  • Zan Jiang
  • Xuehua ZhengEmail author
  • Zhong Li
  • Shuqiong Pan
  • Xiaoyu Wang
  • Chen Zhang
  • Zhe Li
  • Hai-Bin Luo
  • Deyan Wu
  • Xiong Cai
Original Research
  • 3 Downloads

Abstract

Phosphodiesterase-5 (PDE5) inhibitors can be used as clinical agents for the treatment of erectile dysfunction and pulmonary hypertension. A series of aryl-chromeno-pyrrol derivatives were previously identified as PDE5 inhibitors in our lab. Herein, these molecules were subjected to 3D-QSAR analysis with CoMFA and CoMSIA methods to gain deeper insight into the structural requirements for their bioactivities. Receptor- and ligand-based alignment were used and compared to find the alignment-related factors that affect the accuracy of QSAR models. The receptor-based CoMFA and CoMSIA models, which were generated by superimposing the docking conformations directly in the protein binding site, gave more significant results for 38 training set compounds and 5 test set molecules. Comparison of the two alignments revealed that spatial arrangement of the ligands is the principal factor in determining the reliability of the 3D-QSAR models. Detailed analysis of the receptor-based CoMSIA-SE contour maps provided much helpful information to improve the bioactivities of aryl-chromeno-pyrrol analogs as PDE5 inhibitors.

Keywords:

Phosphodiesterase PDE5 inhibitor 3D-QSAR CoMFA CoMSIA 

Notes

Acknowledgements

This work was supported by the Natural Science Foundation of China (81602968); the Natural Science Foundation of Guangdong Province (2016A030313589); the Medical Scientific Research Foundation of Guangdong Province (A2016201); and Science and Technology Program of Guangzhou, China (201707010049); Guangdong provincial Project (2016A020226018).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Andersson KE (2018) PDE5 inhibitors—pharmacology and clinical applications 20 years after sildenafil discovery. Br J Pharmacol 175:2554–2565CrossRefGoogle Scholar
  2. Azzouni F, Abu SK (2011) Are phosphodiesterase type 5 inhibitors associated with vision-threatening adverse events? A critical analysis and review of the literature. J Sex Med 8:2894–2903CrossRefGoogle Scholar
  3. Champion HC, Bivalacqua TJ, Takimoto E, Kass DA, Burnett AL (2005) Phosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism of priapism. Proc Natl Acad Sci USA 102:1661–1666CrossRefGoogle Scholar
  4. Corbin JD, Beasley A, Blount MA, Francis SH (2005) High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors. Biochem Biophys Res Commun 334:930–938CrossRefGoogle Scholar
  5. DeLano W.L. (2002) The PyMOL Molecular Graphics System. De-Lano Scientific, San Carlos, CA, USAGoogle Scholar
  6. Discovery Studio 2. 5.5 (2009). Accelrys Inc., San Diego, CA, USAGoogle Scholar
  7. Fang JS, Huang DN, Zhao WX, Ge H, Luo HB, Xu J (2011) A new protocol for predicting NovelGSK-3 ATP competitive inhibitors. J Chem Inf Model 51:1431–1438CrossRefGoogle Scholar
  8. Francis SH, Blount MA, Corbin JD (2011) Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol Rev 91:651–690CrossRefGoogle Scholar
  9. Golbraikh A, Tropsha A (2002) Beware ofq2! J Mol Graph Model 20:269–276CrossRefGoogle Scholar
  10. Jung JY, Kim SK, Kim BS, Lee SH, Park YS, Kim SJ, Choi C, Yoon SI, Kim JS, Cho SD, Im GJ, Lee SM, Jung JW, Lee YS (2008) The penile erection efficacy of a new phosphodiesterase type 5 inhibitor, mirodenafil (SK3530), in rabbits with acute spinal cord injury. J Vet Med Sci 70:1199–1204CrossRefGoogle Scholar
  11. Keating GM, Scott LJ (2003) Vardenafil: a review of its use in erectile dysfunction. Drugs 63:2673–2703CrossRefGoogle Scholar
  12. Khan AS, Sheikh Z, Khan S, Dwivedi R, Benjamin E (2011) Viagra deafness—sensorineural hearing loss and phosphodiesterase-5 inhibitors. Laryngoscope 21:1049–1054CrossRefGoogle Scholar
  13. Kuschner WG (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353:2148–2157CrossRefGoogle Scholar
  14. Li L, Chen W, Chen T, Ren J, Xu Y (2016) Structure-based discovery of PDEs inhibitors. Curr Top Med Chem 16:917–933CrossRefGoogle Scholar
  15. Oh TY, Kang KK, Ahn BO, Yoo M, Kim WB (2000) Erectogenic effect of the selective phosphodiesterase type 5 inhibitor, DA-8159. Arch Pharm Res 23:471–476CrossRefGoogle Scholar
  16. Ribaudo G, Pagano MA, Bova S, Zagotto G (2016) New therapeutic applications of phosphodiesterase 5 inhibitors (PDE5-Is). Curr Med Chem 23:1239–1249CrossRefGoogle Scholar
  17. Rotella DP (2002) Phosphodiesterase 5 inhibitors: current status and potential applications. Nat Rev Drug Discov 1:674–682CrossRefGoogle Scholar
  18. Sakamoto T, Koga Y, Hikota M, Matsuki K, Murakami M, Kikkawa K, Fujishige K, Kotera J, Omori K, Morimoto H, Yamada K (2014) The discovery of avanafil for the treatment of erectile dysfunction: a novel pyrimidine-5-carboxamide derivative as a potent and highly selective phosphodiesterase 5 inhibitor. Bioorg Med Chem Lett 24:5460–5465CrossRefGoogle Scholar
  19. Scaglione F, Donde S, Hassan TA, Jannini EA (2017) Phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction: pharmacology and clinical impact of the sildenafil citrate orodispersible tablet formulation. Clin Ther 39:370–377CrossRefGoogle Scholar
  20. 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 (2014) 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. Biochem Pharmacol 89:86–98CrossRefGoogle Scholar
  21. Sybyl 7.3 (2006). Tripos Associates, St. Louis, Missouri, USAGoogle Scholar
  22. Tan C, Wu Y, Shao Y, Luo H, Zheng X, Wang L (2017) Docking-based 3D-QSAR studies of phosphodiesterase 9A inhibitors. Lett Drug Des Discov 14:986–998CrossRefGoogle Scholar
  23. Udeoji DU, Schwarz ER (2013) Tadalafil as monotherapy and in combination regimens for the treatment of pulmonary arterial hypertension. Ther Adv Respir Dis 7:39–49CrossRefGoogle Scholar
  24. Unegbu C, Noje C, Coulson JD, Segal JB, Romer L (2017) Pulmonary hypertension therapy and a systematic review of efficacy and safety of PDE-5 inhibitors Pediatrics 139:e20161450CrossRefGoogle Scholar
  25. Wu D, Zhang T, Chen Y, Huang Y, Geng H, Yu Y, Zhang C, Lai Z, Wu Y, Guo X, Chen J, Luo HB (2017) Discovery and optimization of Chromeno[2,3-c]pyrrol-9(2H)-ones as novel selective and orally bioavailable phosphodiesterase 5 inhibitors for the treatment of pulmonary arterial hypertension. J Med Chem 60:6622–6637CrossRefGoogle Scholar
  26. Zheng X, Wu Y, Wu D, Wang X, Zhang C, Guo X, Luo HB (2016) 3D-QSAR studies of 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids as AKR1C3 inhibitors: highlight the importance of molecular docking in conformation generation. Biorg Med Chem Lett 26:5631–5638CrossRefGoogle Scholar
  27. Zheng X, Zhou S, Zhang C, Wu D, Luo HB, Wu Y (2017) Docking-assisted 3D-QSAR studies on xanthones as alpha-glucosidase inhibitors. J Mol Model 23:272CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Chinese Materia MedicaGuangdong Pharmaceutical UniversityGuangzhouChina
  2. 2.Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhouChina
  3. 3.School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhouChina

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