CHROMONE-3-ALDEHYDE DERIVATIVES - SIRTUIN - 2 INHIBITORS IN THE CORRECTION OF MUSCULAR DYSFUNCTION. IN SILICO & IN VIVO STUDY

DOI: https://doi.org/10.29296/25877313-2019-02-07
Issue: 
2
Year: 
2019

V.М. Rukovitsyna Post-graduate Student, Department of Organic Chemistry, Pyatigorsk Medical Pharmaceutical Institute  branch of the FSEI HE «Volgograd State Medical University» E.T. Oganesyan Professor, Dr.Sc. (Pharm.), Head of the Department of Organic Chemistry, Pyatigorsk Medical Pharmaceutical Institute  branch of the FSEI HE «Volgograd State Medical University» D.I. Pozdnyakov Ph.D. (Med.), Senior Lecturer, Department of Pharmacology, Course of Clinical Pharmacology, Pyatigorsk Medical Pharmaceutical Institute  branch of the FSEI HE «Volgograd State Medical University» E-mail: pozdniackow.dmitry@yandex.ru A.V. Voronkov Dr.Sc. (Med.), Associate Professor, Head of the Department of Pharmacology with the Course of Clinical Pharmacology, Pyatigorsk Medical Pharmaceutical Institute  branch of the FSEI HE «Volgograd State Medical University» O.F. Veselova Ph.D. (Med.), Associate Professor, Head of the Department of Pharmacology and Pharmaceutical Consulting, Professor V.F. Voyno-Yasenetsky Krasnoyarsk State Medical University of Ministry of Health of the Russian Federation E.A. Оlokhova Assistant, Department of Pharmacology and Pharmaceutical Consulting, Professor V.F. Voyno-Yasenetsky Krasnoyarsk State Medical University of Ministry of Health of the Russian Federation A.S. Cherapkin Student, Pyatigorsk Medical Pharmaceutical Institute  branch of the FSEI HE «Volgograd State Medical University»

Aim of the study. Evaluate the ability of derived chromone-3-aldehyde to inhibit the function of sirtuin 2 in conditions of muscle dysfunction. Materials and methods. In this work uses an integrated approach by in silico and in vivo tests. In silico prognosis of pharmacological activity (possibility of correction of muscle dysfunction) of new derivatives of chromone-3-aldehyde was carried out using the PASS program. The probabilistic evaluation of the interaction of the studied substances with sirtuin 2 was performed by molecular docking. In vivo study was performed on male Wistar rats, who were modeled muscle dysfunction by electromyostimulation method. The test-objects were administrated per os, prophylactically for 7 days. Af-ter that, biological material (muscle tissue) was taken, in which the level of sirtuin 2 was determined by the ELISA method. Result. As a result, in silico studies found that in a number of studied objects the most pronounced sirtuin 2 inhibitory properties has acyl-substituted derivative of chromone-3-aldehyde, the energy of interaction of the substance with the target molecule was -129,718 kcal/mol. The molecular modeling data were confirmed by the results of in vivo study in which the course application of the acyl-substituted chromone-3-aldehyde derivative re-duced the activity of sirtuin 2 by 218.8% (p

Keywords: 
molecular docking
muscle dysfunction
sirtuins
chromone derivatives

References: 
  1. Maté-Muñoz J.L., Lougedo J.H., Barba M., et. al. Muscular fatigue in response to different modalities of CrossFit sessions // PLoS One. 2017;12(7):e0181855. doi:10.1371/journal.pone.0181855.
  2. Groh W.J. Arrhythmias in the muscular dystrophies // Heart Rhythm. 2012; 9:1890–1895 10.1016/j.hrthm.2012.06.038.
  3. Bann C.M., Abresch R.T., Biesecker B., et al. Measuring quality of life in muscular dystrophy // Neurology. 2015;84 (10):1034-1042.
  4. Sabharwal R. The link between stress disorders and auto-nomic dysfunction in muscular dystrophy // Frontiers in physiology. 2014; 5:25.
  5. Shin J., Tajrishi M.M., Ogura Y., Kumar A. Wasting mechanisms in muscular dystrophy // Int. J. Biochem. Cell. Biol. 2013;45(10):2266-2279.
  6. Arteaga M., Shang N., Ding X., et al. Inhibition of SIRT2 suppresses hepatic fibrosis // Am. J. Physiol. Gastrointest. Liver Physiol. 2016;310(11):G1155- G1168.
  7. Glushko A.A., Voronkov A.V., Kodonidi I.P., Bicherov A.V., Chernikov M.V. Molekuljarnyj doking N-zameschennogo proizvodnogo izohinolonas kataliticheskim domenom C // Farmatsija i farmakologija. 2014; 1(2):3-7. DOI: http://dx.doi.org/ 10.19163/2307-9266-2014-2-1(2)-3-7 (Glushko A.A., Voronkov A.V., Kodonidi I.P., Bicherov A.V., CHernikov M.V. Molekulyarnyj doking N-zameshchennogo proizvodnogo izohinolonas kataliticheskim domenom C // Farmaciya i farmakologiya. 2014; 1(2):3-7. DOI: http://dx.doi.org/ 10.19163/2307-9266-2014-2-1(2)-3-7).
  8. Berman H.M., Westbrook J., Feng Z., Gilliland G., Bhat T.N., Weissig H., Shindyalov I.N., Bourne P.E. The Protein Data Bank // Nucleic Acids Res. 2000; 28(1):235-242.
  9. Teppen B.J. HyperChem, release 2: molecular modeling for the personal computer // J. Chem. Inf. Comput. Sci. 1992; 32:757–759.
  10. Thomsen R., Christensen M.H. MolDock: A new technique for high-accuracy molecular docking // Journal of Medicinal Chemistry. 2006; 49:3315-3321. doi:10.1021/jm051197e.
  11. Gregory N.S., Gibson-Corley K., Frey-Law L., et.al. Fatigue-enhanced hyperalgesia in response to muscle insult: induction and development occur in a sex-dependent manner // Pain. 2013;154(12):2668--2676. doi:10.1016/j.pain.2013.07.047.
  12. Voronkov A.V., Pozdnjakov D.I., Rukovitsina V.M., Oganesjan E.T. Antioksidantnaja aktivnost' novyh pro-izvodnyh hromon-3-al'degida v uslovijah myshechnoj disfunktsii // Voprosy biologicheskoj, meditsinskoj i far matsevticheskoj himii. 2018: 21 (6):38-42 (Voronkov A.V., Pozdnyakov D.I., Rukovicina V.M., Oganesyan EH.T. Antioksidantnaya aktivnost' novyh proizvodnyh hromon-3-al'degida v usloviyah myshechnoj disfunkcii // Voprosy biologicheskoj, medicinskoj i farmacevticheskoj himii. 2018: 21 (6):38-42).
  13. Mellini P., Itoh Y., Tsumoto H., Li Y., Suzuki M., Tokuda M., Kakizawa T., Miura Y., Takeuchi J., Lahtela-Kakkonen M., Suzuki T. Potent mechanism-based sirtuin-2-selective inhibition by an in situ-generated occupant of the substrate-binding site, “selectivity pocket” and NAD+-binding site // Chem. Sci. 2017; 8:6400-6408. doi: 10.1039/C7SC02738A.
  14. Zhang L., Hou X., Ma R., Moley K., Schedl T., Wang Q. Sirt2 functions in spindle organization and chromosome alignment in mouse oocyte meiosis // FASEB J. 2014;28(3):1435-1445.