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Ukr. Bioorg. Acta 2020, Vol. 15, N2, 48-58.

In silico study of biological affinity of nitrogenous bicyclic heterocycles: fragment-to-fragment approach

Yevheniia S. Velihina1, Nataliya V. Obernikhina2*, Stepan G. Pilyo1, Maryna V. Kachaeva1, Oleksiy D. Kachkovsky1, Volodymyr S. Brovarets1

1 V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
2 O. O. Bogomolets National Medical University, 13 Shevchenko Blvd., Kyiv, 01601, Ukraine
tel.: 380-96-225-7764; e-mail: nataliya.obernikhina@gmail.com

ABSTRACT
The biological affinity of model aromatic amino acids and heterocycles and their derivatives condensed with pyridine were carried out in silico and are presented in the framework of fragment-to-fragment approach. The presented model describes interaction between pharmacophores and bio-molecules. Scrupulous data analysis shows that expansion of the π-electron system by heterocycles’ annelation the causes the shifting up of high energy levels, while the appearance of new the di-coordinated nitrogen atom is accompanied by decreasing of the donor-acceptor properties. DFT wB97XD/6-31(d,p)/calculations of possible π-complexes of the heterocycles 1-3 with model fragments of aromatic amino acids, which were formed by π-stack interaction, show an increase in the stabilization energy of π-complexes during the moving from phenylalanine to tryptophan. DFT calculation of pharmacophore complexes with model proton-donor amino acid by the hydrogen bonding mechanism ([H-B] complex) shows that stabilization energy (DE) increases from monoheterocycles to their condensed derivatives. The expansion of the π-electron system of compounds 1a-c by the pyridine cycle reduced the stabilization energy of π-complexes and [H-B] complexes in comparison with the expansion of the π-electronic system by introducing phenyl radicals at positions 2 and 5 of the oxazole ring [18].

KEYWORDS
fragment-to-fragment approach, biological affinity, [Pharm-BioM] complex, π-stacking interaction, hydrogen bonds.

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REFERENCES
1. Yan, X., Wen, J., Zhou, L., Fan, L., Wang, X. and Xu, Z. Current Scenario of 1,3-oxazole Derivatives for Anticancer Activity”, Curr. Top. Med. Chem. 2020, 20 1916-1937.
2. Kakkar, S.; Narasimhan, B. A comprehensive review on biological activities of oxazole derivatives. BMC Chem. 2019, 13, 171-195.
3. Nie, Zh., Perreta, C., Erickson, Ph., Margosiak, S., Lu, J., Averill, A., Almassy, R., Chu, Sh. Structure-based design and synthesis of novel pyrazolo[1,5-a][1,3,5]triazine compounds as potent inhibitors of proteinkinase CK2 and their anticancer activities. Bioorg. Med. Chem. Lett. 2008, 18(2) 619–23.
4. Lamoree, B., Hubbard, R. E. Current perspectives in fragment-based lead discovery (FBLD), Essays Biochem, 2017, 61(5), 453-464.
5. Neto, L. R.S., Moreira-Filho, J. T., Neves, B. J., Maidana, R. L. B. R., Guimaraes, A. C. R., Furnham, N., Andrade, C. H., Silva, F. P. In silico Strategies to Support Fragment-to-Lead Optimization in Drug Discovery. Front. Chem. 2020, 8, 93-102.
6. Bissantz, C., Kuhn, B., Stahl, M. A Medicinal Chemist’s Guide to Molecular Interactions J. Med. Chem. 2010, 53, 5061–5084.
7. Murugavel S., Ravikumar C., Jaabil G., & Alagusundaram P. Synthesis, crystal structure analysis, spectral investigations (NMR, FT-IR, UV), DFT calculations, ADMET studies, molecular docking and anticancer activity of 2-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-4-(2-chlorophenyl)-6-methoxypyridine – A novel potent human topoisomerase II? inhibitor. J. Mol. Str., 2018, 1176, 729–742.
8. Kachaeva, M. V.; Pilyo, S. G.; Zhirnov, V. V.; Brovarets, V. S. Synthesis, characterization, and in vitro anticancer evaluation of 2-substituted 5-arylsulfonyl-1,3-oxazole-4-carbonitriles. Med. Chem. Res. 2019, 28, 71-80.
9. Velihina, Ye., Scattolin, T., Bondar, D., Pil’o, S., Obernikhina, N., Kachkovskyi, O., Semenyuta, I., Caligiuri, I., Rizzolio, F., Brovarets, V., Karpichev, Ye., Nolan, St. P. Synthesis, In silico and In vitro Evaluation of Novel Oxazolopyrimidines as Promising Anticancer Agents, Helv. Chimica Acta, 2020, DOI: 10.1002/hlca.202000169 
10. Christensen, C., Bruun?Schiodt, C., T?kker?Foged, N., Meldal, M. Solid Phase Combinatorial Library of 1,3?Azole Containing Peptides for the Discovery of Matrix Metallo Proteinase Inhibitors, Mol. Inform.2003, 22(7), 754-766.
11. Cherkasov, A., Inductive descriptors: 10 successful years in QSAR. Curr. Comput. Aided Drug Des., 2005, 1, 21–42.
12. Kachaeva, M. V.; Hodyna, D. M.; Semenyuta, I. V.; Pilyo, S. G.; Prokopenko, V. M.; Kovalishyn, V. V.; Metelytsia, L. O.; Brovarets, V. S. Design, synthesis and evaluation of novel sulfonamides as potential anticancer agents. Comput. Biol. Chem. 2018, 74, 294-303.
13. Dahlqvist, A., Leffler, H., Nilsson J. U. C1-Galactopyranosyl Heterocycle Structure Guides Selectivity: Triazoles Prefer Galectin?1 and Oxazoles Prefer Galectin?3. ACS Omega, 2019, 4, 7047?7053.
14. Kachaeva, M. V., Obernikhina, N. V., Veligina, E. S., Zhuravlova, M. Yu., Prostota, Ya. O., Kachkovsky, O. D., Brovarets, V. S.  Estimation of biological affinity of nitrogen-containing conjugated heterocyclic pharmacophores. Chem. Heterocycl. Compd., 2019,55 (4-5), 448–454.
15. Obernikhina, N., Kachaeva, M., Shchodryi, V., Prostota, Ya., Kachkovsky, O., Brovarets, V., & Tkachuk, Z. Topological Index of Conjugated Heterocyclic Compounds as Their Donor/Acceptor Parameter. Polycycl. Aromat. Comp., 2019, 40(4), 1196-1209.
16. Obernikhina, N.V., Nikolaev, R.O., Kachkovsky, O.D., Tkachuk, Z. Yu. ï-electron affinity of the nitrogenous bases of nucleic acids. Dopov. Nac. akad. nauk Ukr., 2019, 6, 75-81.
17. Obernikhina, N.; Pavlenko, O.; Kachkovsky, A.; Brovarets, V. Quantum-Chemical and Experimental Estimation of Non-Bonding Level (Fermi Level) and ?-Electron Affinity of Conjugated Systems. Polycycl. Aromat. Comp. 2020, DOI:10.1080/10406638.2019.1710855
18. Zhuravlova, M.Yu., Obernikhina, N.V., Pilyo, S.G., Kachaeva, M.V., Kachkovsky, O.D., Brovarets, V.S. In silico binding affinity studies of phenyl-substituted 1,3-oxazoles with protein molecules. Ukr. Bioorg. Acta, 2020, 15(1), 12-19.
19. Velihina, Ye. S., Kachaeva, M. V., Pilyo, S. G., Zhirnov, V. V., Brovarets, V. S. Synthesis, Characterization, and In vitro Anticancer Evaluation of 7-Piperazin-Substituted [1,3]Oxazolo[4,5-D]pyrimidines. Der Pharm. Chem., 2018, 10(9), 1-10.
20. Chikkula, K. V., Raja, S. Isoxazole – a potent pharmacophore. Int. J. Phar. and Pharm. Sci., 2017, 9(7), 13–24.
21. Drach, S. V., Litvinovskaya, R. P., Khripach, V. A., Steroidal 1,2-oxazoles. Synthesis and biological activity. (Review). Chem. Heterocycl. Compd, 2000, 36(3), 233–255.
22. Panda, S. S.,  Chowdary, P. V. R, Jayashree, B. S. Synthesis, Antiinflammatory and Antibacterial Activity of Novel Indolyl-isoxazoles, Indian J Pharm. Sci., 2009, 71(6), 684–687.
23. Kaspady, M., Narayanaswamy, V. K., Raju, M., Gopal, K. R., Synthesis, Antibacterial Activity of 2,4-Disubstituted Oxazoles and Thiazoles as Bioisosteres, Lett. Drug Design & Disc., 2009, 6, 21-28.
24. Phatangare, K.R., Borse, B. N., Padalkar, V. S., Patil, V. S., Gupta, V. D., Umape, PR. G., Sekar, N.  Synthesis, photophysical property study of novel fluorescent 4-(1,3-benzoxazol-2-yl)-2-phenylnaphtho[1,2-d][1,3]oxazole derivatives and their antimicrobial activity, J. Chem. Sci., 2013, 125(1), 141–151.
25. Frisch, M.; Trucks, G.; Schlegel, H.; Scuseria, G.; Robb, M.; Cheeseman, J.; Montgomery Jr, J.; Vreven, T.; Kudin, K.; Burant, J. and Millam, J. Gaussian 03, Revision B. 05, Gaussian Inc.: Pittsburgh, PA, Ringraziamenti, 2003.
26. Desiraju, G. R., Steiner, T. The Weak Hydrogen Bond in Structural Chemistry and Biology. Oxford University Press, Oxford, 2010.
27. Zaenger, W. Principles of Nucleic Acid Structure. Springer-Verlag: New-York, Berlin, Heidelberg, Tokyo, 1984.
28. Shapiro, B. I. Molecular assemblies of polymethine dyes. Russ. Chem. Rev. 2006, 75, 433-456.
29. Dewar, M. J. S. The molecular orbital theory of organic chemistry. New York: McGraw Hill, 1969.
30. Obernikhina, N.; Zhuravlova, M.; Kachkovsky, O.; Kobzar, O.; Brovarets, V.; Ðavlenko, O.; Kulish, M.; Dmytrenko, O. Stability of fullerene complexes with oxazoles as biologically active compounds. Appl. Nanosci. 2020, 10, 1345-1353.

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