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Ukr. Bioorg. Acta 2021, Vol. 16, N1, 34-43.

In silico study the interaction of heterocyclic bases with peptide moieties of proteins in «fragment-to-fragment» approach

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

1V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
2O. O. Bogomolets National Medical University, 13 Shevchenko Blvd., Kyiv, 01601, Ukraine

tel.: +380-96-225-7764; e-mail: nataliya.obernikhina@gmail.com

The binding affinity of model peptide moieties (Pept) and heterocyclic bases involving 1,3-oxazoles that are condensed with pyridine and pyrimidine as pharmacophores (Pharm) was investigated in silico and analyzed within the «fragment-to-fragment» approach. The anellation of the heterocyclic rings increasing their acceptor properties is accompanied by gaining stability of the [Pharm-Pept] complexes formed by the π,π-stacking interaction. It was found that elongation of the polypeptide chain led to a twofold increase of the stabilization energy of the [Pharm-Pept] complexes. The stability of the hydrogen bonding ([HB]) [Pharm-BioM] complexes formed by means of the interaction between the dicoordinated nitrogen atom of the heterocycle and the functional groups of peptide amino acids (-OH, -NH2, -SH) was evaluated. It was demonstrated that [HB]-complexes that were formed by hydrogen bonds formation with amino acid that contained OH groups had the largest stabilization effect. The anellation with pyridine and pyrimidine rings led to stability increase of the complexes formed by the hydrogen bonding mechanism. The binding energy of [HB]-complexes for compounds 2b and 3 with a «free» peptide bond of the extended part of the protein is lower compared to amino acids with OH-functional groups. On the contrary, the binding energy of compound 4 with peptides was 2 kcal/mol higher. Compound 4 demonstrated the most pronounced biological activity in vitro studies.

fragment-to-fragment approach; peptide bond; biological affinity; [Pharm-BioM] complex; π,π-stacking interaction; hydrogen bonding.

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1. Kakkar, S.; Narasimhan, B. A comprehensive review on biological activities of oxazole derivatives. BMC Chem. 2019, 13, 171-195.
2. Zhang, H. Z.; Zhao, Z. L.; Zhou, C. H. Recent advance in oxazole-based medicinal chemistry. Eur. J. Med. Chem. 2018, 144, 444-492.
3. Cameron, D. M.; Thompson, J.; March, P. E.; Dahlberg, A. E. Initiation factor IF2, thiostrepton and micrococci in prevent the binding of elongation factor G to the Escherichia coli ribosome. J. Mol. Biol. 2002, 319, 27-35.
4. Rodnina, M. V.; Savelsbergh, A.; Matassova, N. B.; Katunin, V. I.; Semenkov, Yu. P.; Wintermeyer, W. Thiostrepton inhibits the turnover but not the GTPase of elongation factor G on the ribosome. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 9586-9590.
5. Lawrence, D. S.;
Copper, J. E. and Smith C. D. Structure-Activity Studies of Substituted Quinoxalinones as Multiple-Drug-Resistance Antagonists. J. Med. Chem., 2001, 44, 594-601.
6. Borst, P. Multidrug resistance: A solvable problem? Ann. Oncol., 1999, 10, 162-164.
7. Nolt, M. B.; Smiley, M. A.; Varga, S. L.; McClain, R. T.; Wolkenberg, S. E.; & Lindsley, C. W. Convenient preparation of substituted 5-aminooxazoles via a microwave-assisted Cornforth rearrangement. Tetrahedron, 2006, 62, 4698-4704.
8. Fennell, K. A.; & Miller, M. J. Syntheses of Amamistatin Fragments and Determination of Their HDAC and Antitumor Activity, Org. Lett., 2007, 9, 1683-1685.
9. Kachaeva, M. V.; Hodyna, D. M.; Obernikhina, N. V.; Pilyo, S. G.; Kovalenko, Y. S.; Prokopenko, V. M.; Kachkovsky, O. D.; Brovarets, V. S. Design, synthesis and evaluation of novel sulfonamides as potential anticancer agents. J. Heterocycl. Chem. 2019, 56, 3122-3134.
10. Liu, X.; Bai, L.; Pan, C.; Song, B.; Zhu, H. Novel 5-Methyl-2-[(un)substituted phenyl]-4-{4,5-dihydro- 3-[(un)substituted phenyl]-5-(1,2,3,4-tetrahydroisoquinoline-2-yl)pyrazol-1-yl}-oxazole Derivatives: Synthesis and Anticancer Activity. Chin. J. Chem. 2009, 27, 1957-1961.
11. Murphy, G. J.; Holder, J. C. Potential new treatments for type 2 diabetes. Trends. Pharmacol. Sci., 2000, 21, 259-265.
12. Marquez, B. L.; Watts, K. S.; Yokochi, A.; Roberts, M. A.;Verdier-Pinard, P.; Jimenez, J. I.; Hamel, E.; Scheuer, P. J.; Gerwick, W.H. Structure and Absolute Stereochemistry of Hectochlorin, a Potent Stimulator of Actin Assembly. J. Nat. Prod., 2002, 65, 866-871.
13. 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.
14. Dahlqvist, A.; Leffler, H.; Nilsson, U. J. C1-Galactopyranosyl Heterocycle Structure Guides Selectivity: Triazoles Prefer Galectin-1 and Oxazoles Prefer Galectin-3. ACS Omega,  2019, 4, 7047-7053.
15. Youjun Xu., Shiwei W., Qiwan Hu, Shuaishi G., Xiaomin Ma, Weilin Z., Yihang S., Fangjin Ch., Luhua L., Jianfeng P. CavityPlus: a web server for protein cavity detection with pharmacophore modelling, allosteric site identification and covalent ligand binding ability prediction. Nucleic Acids Res.,2018, 46(2), 374-379.
16. Nisius B., Sha F. and Gohlke H. Structure-based computational analysis of protein binding sites for function and druggability prediction. J. Biotechnol., 2012, 159, 123–134.
17. Kasper J.R. and Park C. Ligand Binding to a High-Energy Partially Unfolded Protein. Protein Sci., 2015, 24(1), 129–137.
18. Celej M.S., Guillermo G., Montich G.G. and Fidelio G.D. Protein stability induced by ligand binding correlates with changes in protein flexibility. Protein Sci., 2003, 12(7), 1496–1506.
19. Mortenson P. N., Erlanson D. A., Esch I. J. P., Jahnke W. & Johnson C. N., Fragment-to-Lead Medicinal Chemistry Publications in 2018. J. Med. Chem., 2018, 62(8), 3857-3872.
20. 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.
21. 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.
22. 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, 12-19.
23. Velihina Ye.S.; Obernikhina, N.V.; Pilyo, S.G.; Kachaeva, M.V.; Kachkovsky, O.D.; Brovarets, V.S. In silico study of biological affinity of nitrogenous bicyclic heterocycles: fragment-to-fragment approach. Ukr. Bioorg. Acta 2020, 15(2), 48-58.
24. 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.
25. 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, 448-454.
26. Kachaeva M. V.; Hodyna D. M., Obernikhina N. V., Pilyo S. G., Kovalenko Y. S.,  Prokopenko V. M., Kachkovsky O. D., Brovarets V. S. Dependence of the anticancer activity of 1,3?oxazole derivatives on the donor/acceptor nature of his substitues, J. Heterocyclic Chem., 2019, 56(10), 3122-3134.
27. 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.
28. Jordan, M. The meaning of affinity and the importance of identity in the designed world. Interactions, 2010, 17(5), 6-11.
29. 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.
30. Bissantz C., Kuhn B. and Stahl M. A Medicinal Chemist’s Guide to Molecular Interactions, J. Med. Chem., 2010, 53, 5061–5084.
31. Dewar, M. J. S. The molecular orbital theory of organic chemistry, New York: McGraw Hill, 1969, 484 P.
32. 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, 1196-1209.
33. Obernikhina, N.; Pavlenko, O.; Kachkovsky, A.; Brovarets, V. Quantum-Chemical and Experimental Estimation of Non-Bonding Level (Fermi Level) and π-Electron Affinity of Conjugated Systems. Polycycl. Aromat. Comp. 2020, 2020, 1-10.
34. Palmer T. & Bonner, P. L. The Biosynthesis and Properties of Proteins. Enzymes, 2011, 7, 44-66.
35. Craveur P., Joseph A.P., Poulain, P. et al. Cis–trans isomerization of omega dihedrals in proteins. Amino Acids , 2013, 45, 279-289.

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