Microwave-assisted Solid-phase Synthesis, Biological Evaluation and Molecular Docking of Angiotensin I-converting Enzyme Inhibitors

Abstract

Abstract: Short peptides based on the tripeptides, Leu-Arg-Pro and Leu-Lys-Pro, were synthesized by microwaveassisted solid-phase synthesis method, in order to make a search for potential inhibitors for angiotensin I-converting enzyme(ACE) with minimum side effects in the treatment of hypertension. One peptide with the sequence Leu-Arg-Pro-Phe-Phe shows the strongest inhibition towards ACE with an IC50 value of 0.26 μmol/L in vitro. The study of structure-activity relationship shows that the introduction of a bulky group into the N-terminal of this series of inhibitors may enlarge steric hindrance, resulting in the poor inhibitory activity towards ACE. The inhibitory activity decreased in turn when L-Pro, D-Pro or Ac6c was at the C-terminal respectively. The binding interaction between each of these inhibitors and testicular ACE(tACE) was performed by molecular docking. The results suggest that Leu-Arg-Pro-Phe-Phe mainly occupied the S1 subsite of tACE, and made contact with tACE via seven H-bonds. It appeared that the site on the peptide that bound with tACE was influenced by the configuration of the amino acid, L- or D-form, at the C-terminal of the peptide.

Key words: Angiotensin I-converting enzyme, Peptide inhibitor, Molecular docking, Microwave-assisted solid-phase synthesis

SUN Yang, HUANG Da-wei, LI Xiao-hui, HU Jian-en, XIU Zhi-long. Microwave-assisted Solid-phase Synthesis, Biological Evaluation and Molecular Docking of Angiotensin I-converting Enzyme Inhibitors[J]. Chemical Research in Chinese Universities, 2012, 28(1): 108-113.

References

[1] MacMahon S., Peto R., Cutler J., Collins R., Sorlie P., Neaton J.,Abbott R., God win J., Dyer A., Stamler J., Lancet, 1990, 335, 765 [2] Gradman A. H., Alfayoumi F., Progr. Cardiovasc. Dis., 2006, 48,326 [3] Zaman M. A., Oparil S., Calhoun D. A., Nat. Rev. Drug Discov.,2002, 1, 621 [4] Erdos E. G., Skidgel R. A., Lab. Invest., 1987, 56, 345 [5] Natesh R., Schwager S. L. U., Sturrock E. D., Acharya K. R., Nature,2003, 421(6922), 551 [6] Natesh R., Schwager S. L. U., Evans H. R., Sturrock E. D., Acharya K. R., Biochemistry, 2004, 43(27), 8718 [7] Pina A. S., Roque A. C. A. J., Mol. Recognit., 2009, 22, 162 [8] Corradi H. R., Schwager S. L. U., Nchinda A. T., Sturrock E. D.,Acharya K. R., Mol. Biol., 2006, 357, 964 [9] Junot C. J., Pharmacol., 2001, 297, 606 [10] Ehlers M. R., Fox E. A., Strydom D. J., Riordan J. F., Proc. Natl.Acad. Sci., 1989, 86(20), 7741 [11] FitzGerald R. J., Murray A. M., Walsh D. J., J. Nutr., 2004, 134, 980 [12] van Zwieten P. A., de Jonge A., Timmermans P. B. M. W. M.,Pharm. Weekbl. Sci., 1983, 5, 197 [13] Wu J., Aliko R. E., Nakai S. J., Agric. Food Chem., 2006, 54, 732 [14] Miyoshi S., Ishikawa H., Kaneko T., Fukui F., Tanaka H., Maruyama S., Agric. Biol. Chem., 1991, 55(5), 1313 [15] Fujita H., Yoshikawa M., Immunopharmacology, 1999, 44, 123 [16] Tauzin J., Miclo L., Gaillard J. L., FEBS Lett., 2002, 531, 369 [17] Nakagomi K., Fujimura A., Ebisu H., Sakai T., Sadakane Y., Fujii N., Tanimura T., FEBS Lett., 1998, 438, 255 [18] Meisel H., New Perspectives in Infant Nutrition, Thieme Verlag,New York, 1993, 153 [19] Guang C., Phillips R. D. J., Agric. Food Chem., 2009, 57, 5113 [20] FitzGerald R. J., Meisel H., Br. J. Nutr., 2000, 84, S33 [21] Li G. H., Le G. W., Shi Y. H., Nutrition Research, 2004, 24, 469 [22] Hong F., Ming L., Yi S., Zhan X. L., Yong Q. W., Chi L., Peptides,2008, 29, 1062 [23] Zhao X. H., Xu H. H., Jang Y. J., Food Protien-structure, Propertyand Function, Science Press, Beijing, 2009, 270 [24] Caddick S., Fitzmaurice R., Tetrahedron, 2009, 65, 3325 [25] Kaiser E., Colescott R. L., Bossinger C. D., Anal. Biochem., 1970,34(2), 595 [26] Cushman D. W., Cheung H. S., Biochemistry Pharmacology, 1971,20, 1637 [27] Pripp A. H., Eur. Food Res. Technol., 2007, 225, 589 [28] Creighton T. E., Proteins: Structures and Molecular Properties,2Ed., WH Freeman, New York, 1993 [29] Jimsheena V. K., Gowd L. R., Peptides, 2010, 31, 1165 [30] Chaudhary S., Vats I. D., Chopra M., Biswas P., Pasha S., Bioorg.Med. Chem. Lett., 2009, 19, 4364 [31] Corradi H. R., Chitapi I., Sewell B. T., Georgiadis D., Dive V.,Sturrock E. D., Achiarya K. R., Biochemistry, 2007, 46(18), 5473