Molecular docking and bioavailability of S-alkyl derivatives 5-(3-fluorophenyl)-, 5-(5-bromofuran-2-yl)- and -(((3-(pyridin-4-yl)-1H-1,2,4-triazole-5-yl))thio)methyl)-4-methyl-4H-1,2,4-triazole in silico methods

Authors

  • Ye. O. Karpun Zaporizhzhia State Medical University, Ukraine,
  • Yu. V. Karpenko Zaporizhzhia State Medical University, Ukraine,
  • M. V. Parchenko Zaporizhzhia State Medical University, Ukraine,
  • O. A. Bihdan Zaporizhzhia State Medical University, Ukraine,

DOI:

https://doi.org/10.14739/2409-2932.2020.1.198122

Keywords:

1, 2, 4-triazole, molecular docking simulation, virtual screening, bioavailability

Abstract

The 1,2,4-triazole nucleus is resistant to metabolism and is an important pharmacophore; it can increase solubility and improve the pharmacokinetic and pharmacodynamic profile of drugs. Domestic scientists pay much attention to the heterocyclic 1,2,4-triazole system. A two-component system comprising “EC 2.7.13.3 Histidine kinase” and a variable response protein may be crucial for the virulence of some fungal strains, which are often the cause of candidiasis in immunocompromised individuals. Because of the fact, that humans lack this two-component system, it may be a good target for antimicrobials to treat candidiasis.

The purpose of the study was to carry out a molecular docking and evaluate the bioavailability of S-alkyl derivatives of 5-(3-fluorophenyl)-, 5-(5-bromofuran-2-yl)- and 5‑((((3-(pyridin-4-yl)-1H-1,2,4-triazole-5-yl)thio)methyl)-4-methyl-4H-1,2,4-triazole nucleus in silico by methods promising as objects of biological properties for inhibitors «EC 2.7.13.3 Histidine kinase».

Materials and methods. The synthesis of compounds is carried out according to the well-known method. A virtual screening of compounds was performed using a computer software program PASS. Molecular docking was performed using Autodock 4.2.6. The screening was performed on the crystallographic structure of the enzyme “EC 2.7.13.3 Histidine kinase” (1A0B).

Results. Analysis of the results of a computer prediction demonstrates the prospect of finding inhibitors of histidine kinase, cytidine deaminase, STAT transcription factor, alkaline phosphatase, CYP2C9, insulin, nootropic and diuretic action, antituberculous activity in a number of these compounds. Molecular docking has shown a high affinity of the selected compounds to the enzyme “EC 2.7.13.3 Histidine kinase” with the corresponding values. The interaction of the ligand with the active center of the enzyme is quite complex and is mainly provided by van der Waals and π-bonds with water molecules and amino acid residues of the enzyme. An important point for binding to the enzyme is the presence of Sulfur atoms in the molecules of the test compounds. Based on the above, it is the promising structural modification of the nucleus by the position of the Sulfur atom.

Conclusions. Data from a computer prediction indicate the prospect of searching among the two areas of bioregulators that could be potential histidine kinase inhibitors and diuretic agents. Molecular docking has shown a high affinity of the selected compounds for the “EC 2.7.13.3 Histidine kinase” enzyme, which is provided with van der Waals and π‑bonds with water molecules and amino acid residues of the enzyme.

References

Kaur, R., Kumar, B., Dwivedi, A. R., & Kumar, V. (2016). Regioselective alkylation of 1,2,4-triazole using ionic liquids under microwave conditions. Green Processing and Synthesis, 5(3), 233-237. https://doi.org/10.1515/gps-2015-0138

Parchenko, V. V. (2014). Syntez, peretvorennia, fizyko-khimichni ta biolohichni vlastyvosti v riadi 5-furylzamishchenykh 1,2,4-triazol-3-tioniv (Dis. dokt. farm. nauk). [Synthesis, transformation, physico-chemical and biological properties in the number of 5-furylsubstituted 1,2,4-triazole-3-thiones (Doctoral dissertation)]. Zaporizhzhia State Medical University, Zaporizhzhia. [in Ukrainian].

Parchenko, V. V., Parkhomenko, L. I., Izdepskyi, V. Y., Panasenko, O. I.,  Knysh Ye. H. (2013). Farmakobiokhimichni kharakterystyky piperedynii 2-(5-furan-2-il)-4-fenil-1,2,4-triazol-3-iltioatsetatu [Pharmacological and biochemical characteristics of piperidine 2-(5-furan-2-yl)-4-phenyl-1,2,4-triazol-3-iltioacetate]. Zaporozhye medical journal, (1), 39-41. [in Ukrainian]. https://doi.org/10.14739/2310-1210.2013.1.15453

Knysh, Ye. H. (1987). Sintez, fiziko-khimicheskie i biologicheskie svoistva N- i S-zameshchennykh 1,2,4-triazola (Dis… dokt. farm. nauk) [Synthesis, physicо-chemical and biological properties of N-and S-substituted 1,2,4-triazole (Doctoral dissertation)]. Khar'kov. [in Russian].

Bhate, M. P., Molnar, K. S., Goulian, M., & DeGrado, W. F. (2015). Signal Transduction in Histidine Kinases: Insights from New Structures. Structure, 23(6), 981-994. https://doi.org/10.1016/j.str.2015.04.002

Adam, K., & Hunter, T. (2018). Histidine kinases and the missing phosphoproteome from prokaryotes to eukaryotes. Laboratory Investigation, 98(2), 233-247. https://doi.org/10.1038/labinvest.2017.118

Parchenko, V. V., Yerokhin, V. Ye., Panasenko, O. I.,  Knysh Ye. H. (2010). Syntez, peretvorennia, fizyko-khimichni vlastyvosti 4-alkil-, aryl-ta 4-aminopokhidnykh 1,2,4-tryazol-3-tioliv iz zalyshkamy frahmentiv furanu [Synthesis, transformation, physicochemical properties of 4-alkyl-, aryl- and 4-amino-1,2,4-triazole-3-thiols with residues of furan fragments]. Zaporozhye medical journal, 12(4), 83-87. [in Ukrainian].

Parchenko, V. V., Panasenko, O. I.,  Knish, E. G. (2012). Synthesis, physical and chemical properties of some derivatives 1,2,4-triazolo-(3,4-b)-1,3,4-thiodiazine with residue of fragments of furan. Intellectual Archive, 1(7), 63-72.

Filimonov, D. A., Druzhilovskiy, D. S., Lagunin, A. A., Gloriozova, T. A., Rudik, A. V., Dmitriev, A. V., … Poroikov, V. V. (2018). Komp'yuternoe prognozirovanie spektrov biologicheskoi aktivnosti khimicheskikh soedinenii: vozmozhnosti i ogranicheniya [Computer-aided prediction of biological activity spectra for chemical compounds: opportunities and limitations]. Biomedical Chemistry: Research and Methods, 1(1), e00004. [in Russian]. https://doi.org/10.18097/bmcrm00004

Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility. Journal of Computational Chemistry, 30(16), 2785-2791. https://doi.org/10.1002/jcc.21256

de Backer, M. M. E., McSweeney, S., Lindley, P. F., & Hough, E. (2004). Ligand-binding and metal-exchange crystallographic studies on shrimp alkaline phosphatase. Acta Crystallographica Section D-Structural Biology, 60, 1555-1561. https://doi.org/10.1107/s0907444904015628

Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7. https://doi.org/10.1038/srep42717

Ritchie, T. J., Ertl, P., & Lewis, R. (2011). The graphical representation of ADME-related molecule properties for medicinal chemists. Drug Discovery Today, 16(1-2), 65-72. https://doi.org/10.1016/j.drudis.2010.11.002

Lovering, F., Bikker, J., & Humblet, C. (2009). Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. Journal of Medicinal Chemistry, 52(21), 6752-6756. https://doi.org/10.1021/jm901241e

Published

2023-11-17

How to Cite

1.
Karpun YO, Karpenko YV, Parchenko MV, Bihdan OA. Molecular docking and bioavailability of S-alkyl derivatives 5-(3-fluorophenyl)-, 5-(5-bromofuran-2-yl)- and -(((3-(pyridin-4-yl)-1H-1,2,4-triazole-5-yl))thio)methyl)-4-methyl-4H-1,2,4-triazole in silico methods. Current issues in pharmacy and medicine: science and practice [Internet]. 2023Nov.17 [cited 2024May24];13(1). Available from: http://pharmed.zsmu.edu.ua/article/view/198122

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Section

Original research