In silico study of new bis-3R, 4R′-5-(((1H-1,2,4-triazole-5-yl)thio)methyl)-4H-1,2,4-triazole-3-thione derivatives
Keywords:triazoles, synthesis, molecular docking simulations, virtual screening
A combination of two rings of 1,2,4-triazole with the formation of new hybrids, bis-1,2,4-triazoles, with various functional groups and pharmacophores may comprise a promising class of the biologically active compounds. Alkaline phosphatases belong to a broad family of enzymes, ectonucleotidases, which are responsible for the dephosphorylation of nucleoside phosphates and have an impact on the metabolic processes in the organism.
The purpose of this work was to conduct virtual screening and molecular docking of the initial 4-alkyl-5-(((3-(pyridine-4-yl)-1H-1,2,4-triazole-5-yl)thio)methyl)-4H-1,2,4-triazole-3-thiols, which are promising bioactive compounds capable of inhibiting alkaline phosphatase.
Materials and methods. All compounds were synthesized by the general method. Virtual screening was held using PASS software. Molecular docking research was done using Autodock 4.2.6 software. The screening was held on the crystallographic structure of the “EC 184.108.40.206 Alkaline phosphatase” (1SHN) enzyme.
Results. The analysis of the computer-based prognosis demonstrated that the research of the inhibition of alkaline phosphatase, histininkinase, nucleotide and phosphatase metabolism, diuretic and antineoplastic properties among these compounds is relevant. The compounds exhibit a wide array of biological activities, among which the inhibition of alkaline phosphatase and antitumor activity are the most immediate. Molecular docking was showed that the compounds had a high affinity to the “EC 220.127.116.11 Alkaline phosphatase” (1SHN) enzyme, specifically -7.08 kcal/mol and -7.88 kcal/mol, respectively. It was established that Carbon atoms at the 4-position of 1,2,4-triazole reacted with water molecules (using hydrogen bond) and the amino acid residue of the THR B:435. The Carbon was acted as an electron donor in the hydrogen bond with the relation of -Alkyl to THR B:435 (2.11 Å). According to this research, this structural modification of 1,2,4-triazole is promising.
Conclusions. The data of computer prognosis show promise the search of bioregulators among the studied compounds on two promising directions: alkaline phosphatase inhibition and antineoplastic activity. Molecular docking was showed the high affinity of the selected compounds to the “EC 18.104.22.168 Alkaline phosphatase” (1SHN) enzyme, which may be present due to water molecules (using hydrogen bond) and the amino acid residue of the threonine, high number of hydrophobic bonds, negatively and positively charged particles, and polar bonds.
Rao, D. (2015). Synthesis, Characterization and Antimicrobial Evaluation of Substituted 1,2,4-Triazole Thiones Containing Pyrazole Moiety. Journal Of Clinical And Analytical Medicine, 6(5). doi: 10.4328/jcam.2323
Parchenko, V. V. (2014). Syntez, peretvorennia, fizyko-khimichni ta biolo¬hichni 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 Dr. farm. sci. diss.]. 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. doi: https://doi.org/10.14739/2310-1210.2013.1.15453 [in Ukrainian].
Knysh Ye. H. (1987). Sintez, fiziko-himicheskie i biologicheskie svojstva N- i S-zameshhennyh 1,2,4-triazola (Dis… dokt. farm. nauk) [Synthesis, physicо-chemical and biological properties of N-and S-substituted 1, 2, 4-triazole Dr. farm. sci. diss.]. Kharkiv. [in Russian].
Millán, J. (2006). Alkaline Phosphatases. Purinergic Signalling, 2(2), 335-341. doi: 10.1007/s11302-005-5435-6
Coleman, J. (1992). Structure and Mechanism of Alkaline Phosphatase. Annual Review Of Biophysics And Biomolecular Structure, 21(1), 441-483. doi: 10.1146/annurev.biophys.21.1.441
Pabis, A., & Kamerlin, S. (2016). Promiscuity and electrostatic flexibility in the alkaline phosphatase superfamily. Current Opinion In Structural Biology, 37, 14-21. doi: 10.1016/j.sbi.2015.11.008
Mornet, E., Stura, E., Lia-Baldini, A., Stigbrand, T., Ménez, A., & Le Du, M. (2001). Structural evidence for a functional role of human tissue nonspecific alkaline phosphatase in bone mineralization. Journal Of Biological Chemistry, 276(33), 31171-31178. doi: 10.1074/jbc.m102788200
Hessle, L., Johnson, K., Anderson, H., Narisawa, S., Sali, A., & Goding, J. et al. (2002). Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Proceedings Of The National Academy Of Sciences, 99(14), 9445-9449. doi: 10.1073/pnas.142063399
Lallès, J. (2010). Intestinal alkaline phosphatase: multiple biological roles in maintenance of intestinal homeostasis and modulation by diet. Nutrition Reviews, 68(6), 323-332. doi: 10.1111/j.1753-4887.2010.00292.x
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-triazol-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.
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., Druzhilovskiy, D., Lagunin, A., Gloriozova, T., Rudik, A., & Dmitriev, A. et al. (2018). Computer-aided prediction of biological activity spectra for chemical compounds: opportunities and limitation. Biomedical Chemistry: Research And Methods, 1(1), e00004. doi: 10.18097/bmcrm00004
Morris, G., Huey, R., Lindstrom, W., Sanner, M., Belew, R., Goodsell, D., & Olson, A. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal Of Computational Chemistry, 30(16), 2785-2791. doi: 10.1002/jcc.21256
De Backer, M., McSweeney, S., Lindley, P., & Hough, E. (2004). Ligand-binding and metal-exchange crystallographic studies on shrimp alkaline phosphatase. Acta Crystallographica Section D Biological Crystallography, 60(9), 1555-1561. doi: 10.1107/s0907444904015628
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