IN SILICO RESEARCH OF THE POSSIBLE PATHWAYS OF ATRISTAMINE METABOLISM IN THE HUMAN BODY

Authors

  • I. M. Podolsky NATIONAL UNIVERSITY OF PHARMACY, KHARKIV
  • S. Yu. Shtrygol NATIONAL UNIVERSITY OF PHARMACY, KHARKIV

DOI:

https://doi.org/10.11603/mcch.2410-681X.2019.v.i3.10558

Keywords:

atristamine, 2-methyl-3-(phenylaminomethyl)-1H-quinolin-4-one, metabolism, in silico research, Xenosite, Way2Drug

Abstract

Introduction. The object of the present study is atristamine (2-methyl-3-(phenylaminomethyl)-1H-quinolin-4-one), which is being studied as a promising antidepressant with cerebroprotective, nootropic, analgesic, antihypoxic and actoprotective properties. A prerequisite for its further introduction as a candidate for drugs is the study of the pharmacokinetic characteristics of the molecule. This is impossible without a holistic understanding of the biotransformation processes that the molecule undergoes in the human body.

The aim of the study – in silico study of the possible metaboliс pathways of the promising antidepressant atristamine using freely available online resources.

Research Methods. For the purpose of in silico research of possible directions of biotransformation of atristamine in the human body, the following online web services were used: Xenosite P450 Metabolism 1.0; Xenosite UGT 2.0; Way2Drug SOMP and Way2Drug RA. Taking into account that the structural feature of quinolin-4(1H)-ones is the possibility of prototropic tautomerism in the heterocycle, computations were performed for both theoretically possible tautomeric forms of the atristamine molecule – 2-methyl-3-(phenylaminomethyl)-1H-quinolin-4-one and 4-hydroxy-2-methyl-3-(phenylaminomethyl)-quinoline.

Results and Discussion. Due to the presence of a secondary amino group in the molecule of 2-methyl-3-(phenylaminomethyl)-1H-quinolin-4-one and 4-hydroxy group in the structure of another tautomer (4-hydroxy-2-methyl-3-(phenylaminomethyl)-quinoline) glucuronidation is highly probable with the formation of N- and O-glu­curonides, respectively. For 2-methyl-3-(phenylaminomethyl)-1H-quinolin-4-one as a more stable form, it was shown that aromatic hydroxylation, aliphatic hydroxylation, oxidative deamination, N-hydroxylation and epoxidation can be the main metabolic pathways. The direction of aliphatic hydroxylation deserves the most attention, since, unlike all other pathways, the formation of metabolites with new pharmacological properties (kynurenic acid derivatives) was predicted as a result of this.

Conclusions. The results of in silico research of possible pathways of atristamine metabolism in the human body support the fact that this molecule with high probability can be intensively metabolized via cytochrome P450 enzyme systems. This must be taken into account when planning in vivo experiments in the future.

References

Rudik, A.V., Dmitriev, A.V., Lagunin, A.A., Filimonov, D.A., & Poroikov, V.V. (2016). Prediction of reacting atoms for the major biotransformation reactions of organic xenobiotics. J. Cheminformatics, 8, Art. No. 68. Retrieved from: https://doi.org/10.1186/s13321-016-0183-x DOI: https://doi.org/10.1186/s13321-016-0183-x

Kirchmair, J., Göller, A.H., Lang, D., Kunze, J., Testa, B., Wilson, I.D., … Schneider, G. (2015). Predicting drug metabolism: experiment and/or computation? Nat. Rev. Drug Discov., 14 (6), 387-404. Retrieved from: https://doi.org/10.1038/nrd4581 DOI: https://doi.org/10.1038/nrd4581

Adams, S.E. (2010). Molecular similarity and xenobiotic metabolism (Doctoral thesis). Retrieved from: https://doi.org/10.17863/CAM.16274

Caira, M.R., & Ionescu, C. (2005). Drug Metabolism: Current Concepts. Springer Netherlands. Retrieved from: https://doi.org/10.1007/1-4020-4142-X DOI: https://doi.org/10.1007/1-4020-4142-X

Delannée, V., Langouët, S., Siegel, A., & Théret, N. (2019). In silico prediction of Heterocyclic Aromatic Amines metabolism susceptible to form DNA adducts in humans. Toxicology Letters, 300, 18-30. Retrieved from: https://doi.org/10.1016/j.toxlet.2018.10.011 DOI: https://doi.org/10.1016/j.toxlet.2018.10.011

Tyzack, J.D., Mussa, H.Y., Williamson M.J., Kirchmair, J., Glen, R.C. (2014). Cytochrome P450 site of metabolism prediction from 2D topological fingerprints using GPU accelerated probabilistic classifiers. Retrieved from: J. Cheminformatics, 6, Art. №29. Retrieved from: https://doi.org/10.1186/1758-2946-6-29 DOI: https://doi.org/10.1186/1758-2946-6-29

Zaretzki, J., Matlock, M., Swamidass, S.J. (2013). XenoSite: accurately predicting CYP-mediated sites of metabolism with neural networks. J. Chem. Inf. Model., 53(12), 3373-3383. Retrieved from: https://doi.org/10.1021/ci400518g DOI: https://doi.org/10.1021/ci400518g

Dang, N.L., Hughes, T.B., Krishnamurthy, V., Swamidass, S.J. (2016). A simple model predicts UGT-mediated metabolism. Bioinformatics, 32 (20), 3183-3189. Retrieved from: https://doi.org/10.1093/bioinformatics/btw350 DOI: https://doi.org/10.1093/bioinformatics/btw350

Rudik, A., Dmitriev, A., Lagunin, A., Filimonov, D., Poroikov, V. (2015). SOMP: web server for in silico prediction of sites of metabolism for drug-like compounds. Bioinformatics, 31 (12), 2046-2048. Retrieved from: https://doi.org/10.1093/bioinformatics/btv087 DOI: https://doi.org/10.1093/bioinformatics/btv087

Shtrygol, S.Yu., Zubkov, V.A., Podolskiy, I.N., & Gritsenko, I.S. (2012). 2-Metil-3-fenilaminometilkhinolin-4-on – potentsialnyy antidepressant s nootropnymi svoystvami [2-Methyl-3-phenylaminomethylquinolin-4-one as potential antidepressant with nootropic properties]. Eksperimentalnaya i klinicheskaya farmakologiya – Experimental and Clinical Pharmacology, 75 (4), 7-9 [in Russian].

Podolsky, I.M., Shtrygol′, S.Yu., & Zubkov, V.O. (2018). The psycho- and neurotropic profiling of novel 3-(N-R,R′-aminomethyl)-2-methyl-1H-quinolin-4-ones in vivo. Saudi Pharmaceutical Journal, 26 (1), 107-114. Retrieved from: https://doi.org/10.1016/j.jsps.2017.10.005 DOI: https://doi.org/10.1016/j.jsps.2017.10.005

Podolsky, I.M., & Shtrygol, S.Yu. (2015). Neuroprotective activity of 2-methyl-3-phenylaminomethylquinolin-4-one in experimental traumatic brain injury in rats. Journal of Chemical and Pharmaceutical Research, 7 (4), 518-524.

Podolsky, I., Shtrygol', S. (2019). The memory and learning enhancing effects of Atristamine. Pharmacia, 66 (1), 13-18. Retrieved from: https://doi.org/10.3897/pharmacia.66.e35048 DOI: https://doi.org/10.3897/pharmacia.66.e35048

Podolsky, I., Shtrygol', S. (2017). The analgesic properties of a promising antidepressant – 2-methyl-3-(phenylaminomethyl)-1H-quinolin-4-one. The Pharma Innovation Journal, 6 (8C), 156-160.

Podolskyi, I.M., Shtryhol, S.Yu., Ostashko, V.F., & Bezditko, N.V. (2013). Doslidzhennia antyhipoksychnoi aktyvnosti 2-metyl-3-fenilaminometylkhinolin-4-onu – perspektyvnoho antydepresanta z nootropnymy vlastyvostiamy [The research of antihypoxic activity of 2-methyl-3-phenylaminomethylquinolin-4-one – perspective antidepressant with nootropic properties]. Ukrainskyi biofarmatsevtychnyi zhurnal – Ukrainian Biopharmaceutical Journal, 2 (25), 46-49 [in Ukrainian].

Zubkov, V.O., Rozhenko, О.B., Ruschak, N.I., & Gritsenko, I.S. (2016). The experimental and theoretical study of tautomerism of 3-substituted 2-methyl-quinoline-4(1H)-ones. Zhurnal orhanichnoi ta farmatsevtychnoi khimii – Journal of Organic and Pharmaceutical Che­mistry, 14 (2), 53-59. DOI: https://doi.org/10.24959/ophcj.16.892

Lovelace, M.D., Varney, B., Sundaram, G., Lennon, M.J., Lim, C.K., Jacobs, K., … Brew, B.J. (2017). Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological di­seases. Neuropharmacology, 112 (B), 373-388. Re­trie­ved from: https://doi.org/10.1016/j.neuropharm.2016.03.024 DOI: https://doi.org/10.1016/j.neuropharm.2016.03.024

Published

2019-11-07

How to Cite

Podolsky, I. M., & Shtrygol, S. Y. (2019). IN SILICO RESEARCH OF THE POSSIBLE PATHWAYS OF ATRISTAMINE METABOLISM IN THE HUMAN BODY. Medical and Clinical Chemistry, (3), 44–52. https://doi.org/10.11603/mcch.2410-681X.2019.v.i3.10558

Issue

Section

ORIGINAL INVESTIGATIONS