Molecular study of mechanisms of action of cilostazol on certain families of phosphodiesterases

• Koreyba K.A.
• Stupin V.A.
• Silina E.V.
• Syuzev K.N.
• Serebryakova O.A.

Abstract

Objective. The purpose of the study was to examine the effect of cilostazol on isoforms of targets of phosphodiesterase 3 and phosphodiesterase 5 by means of molecular modeling.

Material and methods. Inhibition of phosphodiesterases (PDEs) was studied by means of molecular docking using software Maestro Schrodinger Inc. The structure of all mentioned proteins was taken from the Protein Data Bank (PDB): 7L27-PDE3A, 1JOS-PDE3B, 4MD6-PDE5. The structures of cilostazol and vardenafil ligands were obtained from the PubChem database. The Glide Docking SP mode was used to determine the best pose of the ligand in the supramolecular complex PDE-ligand with the function of minimal assessment of energy. The structures of PDEs were taken from protein database. Each molecule of PDE was prepared before docking using the Protein Preparation Wizard module. The ligand geometry was optimized using the force field MMF4 in the software package of molecular dynamics GROMACS. The active center of enzymes was considered rigid, with the change of torsion angles being allowed for cilostazol. The results were visualized using the function Ligand Interaction in the Maestro module. The inhibition constant (Ki) was obtained from the binding energy (ΔG) using the formula: Ki=exp (ΔG/RT), where R is the universal gas constant (1.985 × 10⁻³ kcal · mol^{− 1} · K⁻¹) and T is the temperature (298.15 К).

Results. Cilostazol possesses higher affinity to isoform of PDE3A (Ki=54 nM) as compared with PDE3B (Ki=1.13 µM) based on the findings of the performed molecular docking. Also, cilostazol can inhibit PDE5 in therapeutic doses (Ki=10 µM).

Conclusion. Cilostazol-mediated inhibition of the isoform PDE3A to a greater degree than PDE3B explains a low incidence of side effects from the side of PDE3B inhibition in clinical practice. Cilostazol may also inhibit PDE5 at therapeutic doses (Ki=10 µM), in which connection it may have an additional therapeutic effect in treatment of intermittent claudication, diabetes mellitus and its complications, especially neuropathy.

Funding. The study had no sponsor support.

Conflict of interest. The authors declare no conflict of interest.

For citation: Koreyba K.A., Stupin V.A., Silina E.V., Syuzev K.N., Serebryakova O.A. Molecular study of mechanisms of action of cilostazol on certain families of phosphodiesterases. Angiology and Vascular Surgery. 2022; 28 (1): 22–8. DOI: https://doi.org/10.33029/1027-6661-2022-28-1-22-28 (in Russian)

Keywords:diabetes mellitus; diabetic foot syndrome; chronic arterial insufficiency; phosphodiesterase inhibitor; cilostazol; molecular modeling

References

1. International Diabetes Federation. IDF Diabetes Atlas, 10^th ed. Brussels, Belgium: International Diabetes Federation. 2021.

2. Яковлев А.В., Яковлева О.В., Ситдикова Г.Ф. Учебное пособие. Аденилатциклазная и гуанилатциклазная системы внутриклеточных вторичных посредников. Казань: Издательство КГУ. 2009; 48. [Yakovlev AV, Yakovleva OV, Sitdikova GF. Uchebnoe posobie. Adenilattsiklaznaya i guanilattsiklaznaya sistemy vnutrikletochnykh vtorichnykh posrednikov. Kazan’: Izdatel’stvo KGU. 2009; 48. (In Russ.)]

3. Liras S, Bell AS, Mannhold R, et al. Phosphodiesterases and their inhibitors. Weinheim, Germany: John Wiley & Sons. 2014; 240.

4. Francis SH, Blount MA, Corbin JD. Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol Rev. 2011; 91 (2): 651–690. doi: 10.1152/physrev.00030.2010

5. Sun B, Li H, Shakur Y, et al. Role of phosphodiesterase type 3A and 3B in regulating platelet and cardiac function using subtype-selective knockout mice. Cell Signal. 2007; 19: 1765–1771. doi: 10.1016/j.cellsig.2007.03.012

6. Kilanowska A, Ziółkowska A. Role of phosphodiesterase in the biology and pathology of diabetes. Int J Mol Sci. 2020; 21 (21): 8244. doi: 10.3390/ijms21218244

7. Friesner RA, Murphy RB, Repasky MP, et al. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem. 2006; 49 (21): 6177–6196. doi: 10.1021/jm051256o

8. Berendsen HJC, van der Spoel D, van Drunen R. GROMACS: A message-passing parallel molecular dynamics implementation. Comp Phys Comm. 1995; 91 (1–3): 43–56. doi: 10.1016/0010-4655(95)00042-E

9. Atkins PW, Paula JC. Physical chemistry. Oxford: Oxford University Press. 2006; 944.

10. Maurice DH, Ke H, Ahmad F, et al. Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov. 2014; 13 (4): 290–314. doi: 10.1038/nrd4228

11. Ahmad F, Chung YW, Tang Y, et al. Phosphodiesterase 3B (PDE3B) regulates NLRP3 inflammasome in adipose tissue. Sci Rep. 2016; 6: 28056. doi: 10.1038/srep28056

12. Wang L, Chopp M, Zhang ZG. PDE5 inhibitors promote recovery of peripheral neuropathy in diabetic mice. Neural Regen Res. 2017; 12 (2): 218–219. doi: 10.4103/1673-5374.200804

13. Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006; 58 (3): 488–520. doi: 10.1124/pr.58.3.5

14. Yan C, Miller CL, Abe J. Regulation of phosphodiesterase 3 and inducible cAMP early repressor in the heart. Circ Res. 2007; 100 (4): 489–501. doi: 10.1161/01.RES.0000258451. 44949.d7

15. Polidovitch N, Yang S, Sun H, et al. Phosphodiesterase type 3A (PDE3A), but not type 3B (PDE3B), contributes to the adverse cardiac remodeling induced by pressure overload. J Mol Cell Cardiol. 2019; 132: 60–70. doi: 10.1016/j.yjmcc.2019.04.028

16. Kherallah RY, Khawaja M, Olson M, et al. Cilostazol: a review of basic mechanisms and clinical uses. Cardiovasc Drugs Ther. 2021. doi: 10.1007/s10557-021-07187-x

17. Wise SK, Lin SY, Toskala E, et al. International consensus statement on allergy and rhinology: allergic rhinitis. Int Forum Allergy Rhinol. 2018; 8 (2): 108–352. doi: 10.1002/alr.22073

18. Conti M. Phosphodiesterases and regulation of female reproductive function. Curr Opin Pharmacol. 2011; 11: 665–669.

19. Chapman TM, Goa KL. Cilostazol: a review of its use in intermittent claudication. Am J Cardiovasc Drugs. 2003; 3 (2): 117–138. doi: 10.2165/00129784-200303020-00006

20. Arroyo A, Kim B, Yeh J. Luteinizing hormone action in human oocyte maturation and quality: signaling pathways, regulation, and clinical impact. Reprod Sci. 2020; 27 (6): 1223–1252. doi: 10.1007/s43032-019-00137-x

21. Härndahl L, Wierup N, Enerbäck S, et al. Beta-cell-targeted overexpression of phosphodiesterase 3B in mice causes impaired insulin secretion, glucose intolerance, and deranged islet morphology. J Biol Chem. 2004; 279 (15): 15214–15222. doi: 10.1074/jbc.M3089 52200

22. Hsieh CJ, Wang PW. Effect of cilostazol treatment on adiponectin and soluble CD40 ligand levels in diabetic patients with peripheral arterial occlusion disease. Circ J. 2009; 73 (5): 948–954. doi: 10.1253/circj.cj-08-0905

23. Andersson KE. PDE5 inhibitors – pharmacology and clinical applications 20 years after sildenafil discovery. Br J Pharmacol. 2018; 175 (13): 2554–2565. doi: 10.1111/bph.14205

24. Padda IS, Tripp J. Phosphodiesterase Inhibitors. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021.

All articles in our journal are distributed under the CC BY-NC-ND 4.0 (Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International)

п?? GEOTAR-Media Publishing Group. The use of textual and illustrative content from this publication for the training of any artificial intelligence systems п?? including machine learning models and neural networks п?? is strictly prohibited without the prior written consent of the copyright holder.