New ACE Inhibitor Designed from Nicotianamine and Its Docking Pose Prediction Using the Gold Program
Journal of Drug Design and Medicinal Chemistry
Volume 5, Issue 3, September 2019, Pages: 33-39
Received: Jul. 16, 2019; Accepted: Aug. 7, 2019; Published: Aug. 23, 2019
Views 442      Downloads 176
Noboru Takada, Faculty of Agriculture and Life Science, Hirosaki University, Hirosaki, Japan
Takaharu Okada, Faculty of Agriculture and Life Science, Hirosaki University, Hirosaki, Japan
Eri Kogawa, Faculty of Agriculture and Life Science, Hirosaki University, Hirosaki, Japan
Yohsuke Sanada, Faculty of Agriculture and Life Science, Hirosaki University, Hirosaki, Japan
Ayumi Ishidoya, Faculty of Agriculture and Life Science, Hirosaki University, Hirosaki, Japan
Article Tools
Follow on us
Hypertension is currently one of the most serious health issues worldwide. Nicotianamine, a non-peptide-type amino acid trimer, is ubiquitously present in higher plants and plays a role as an internal metal transporter. It is known that nicotianamine inhibits ACE activity and that oral treatment with the compound improves hypertension. However the mode of action remains unclear, due to lack of crystallographic data. Although a structure-activity relationship study of nicotianamine has the potential to uncover the details of the inhibition profile, the azetidine-2-carboxylic acid moiety in nicotianamine has become a critical barrier for further biochemical research due to limited commercial supply and difficulties with structural modification. In this paper, ten nicotianamine analogs without azetidine-2-carboxylic acid moiety were prepared and their inhibition of angiotensin I-converting enzyme was investigated. Among these analogs, a phenylalanine analog, (2S,3′S,3″S)-N-{3′-(3″-amino-3″-carboxypropylamino)-3′-carboxypropyl}phenylalanine, displayed the most potent activity. The inhibition activity of the compound corresponded to that of captopril. These results suggested a possibility of structural modification of nicotianamie to develop antihypertensive drugs. Molecular docking studies with Gold were also performed to predict the binding poses of nicotianamine and its analog, suggesting that nicotianamine and its analogs combine a plausible allosteric site in an area away from the catalytic site in ACE.
Nicotianamine, Structure-Activity-Relationship Study, Angiotensin I-Converting Enzyme Inhibitors, Molecular Docking Study, Allosteric Binding Site
To cite this article
Noboru Takada, Takaharu Okada, Eri Kogawa, Yohsuke Sanada, Ayumi Ishidoya, New ACE Inhibitor Designed from Nicotianamine and Its Docking Pose Prediction Using the Gold Program, Journal of Drug Design and Medicinal Chemistry. Vol. 5, No. 3, 2019, pp. 33-39. doi: 10.11648/j.jddmc.20190503.11
Copyright © 2019 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License ( which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
M. A. Ondetti, B. Rubin D. W. Cushman Design of specific inhibitors of angiotensin converting enzyme; new class of orally active antihypertensive agents. Science, Vol 196, 1977, pp 441-444.
A. B. AtkinsonJ. I. S. Robertson Captopril in the treatment of clinical hypertension and cardiac failure. Lancet, Vol 314, 1979, pp 836-839.
E. M. Salar, S. I. Bastacky, E. K. JacksonS. P. Tofovic Captopril attenuates cardiovascular and renal disease in a rat model of heart failure with preserved ejection fraction. J. Cardiovasc. Pharmacol., Vol 71, 2018, pp 205-214.
R. Natesh, S. L. U. Schwager, H. R. Evans, E. D. SturrockK. R. Acharya Structural details on the binding of antihypertensive drugs captopril and enalaprilat to human testicular angiotensin I-converting enzyme. Biochemistry, Vol 43, 2004, pp 8718-8724.
A. A. Patchett, E. Harris, E. W. Tristram, M. J. Wyvratt, M. T. Wu, D. Taub, E. R. Peterson, T. J. Ikeler, J. ten Broeke, L. G. Payne, D. L. Ondeyka, E. D. Thorsett, W. J. Greenlee, N. S. Lohr, R. D. Hoffsommer, H. Joshua, W. V. Ruyle, J. W. Rothrock, S. D. Aster, A. L. Maycock, F. M. Robinson, R. Hirschmann, C. S. Sweet, E. H. Ulm, D. M. Gross, T. C. VassilC. A. Stone A new class of angiotensin-converting enzyme inhibitors. Nature, Vol 288, 1980, pp 280-283.
M. Noma, M. NoguchiE. Tamaki A new amino acid, nicotianamine, from tabacco leaves. Tetrahedron Lett., Vol 12, 1971, pp 2017-2020.
M. Takahashi, Y. Terada, I. Nakai, H. Nakanishi, E. Yoshimura, S. MoriN. K. Nishizawa Role of nicotianamine in the intracellular delivery of metals and plant reproductive development. Plant Cell, Vol 15, 2003, pp 1263-1280.
R. K. Kumar, H. -H. Chu, C. Abundis, K. Vasques, D. C. Rodriguez, J. -C. Chia, R. Huang, O. K. VatamaniukE. L. Walker Iron-nicotianamine transporters are required for proper long distance iron signaling. Plant Physiol., Vol 175, 2017, pp 1254-1268.
T. Nozoye, M. Otani, T. Senoura, H. NakanishiN. K. Nishizawa Overexpression of barley nicotianamine synthase 1 confers tolerance in the sweet potato to iron deficiency in calcareous soil. Plant Soil, Vol 418, 2017, pp 75-88.
E. Kinoshita, J. YamakoshiM. Kikuchi Purification and identification of an angiotensin I-converting enzyme inhibitor from soy sauce. Biosci. Biotechnol. Biochem., Vol 57, 1993, pp 1107-1110.
A. Hayashi, T. Nakayama, K. Murakami, Y. AoyagiK. Kimoto Effects of nicotianamine on blood pressure in Tsukuba hypertensive mice (THM). J. Jpn. Soc. Nutr. Food Sci., Vol 58, 2005, pp 315-321.
S. Takahashi, T. Yoshiya, K. Yoshizawa-KumagayeT. Sugiyama Nicotianamine is a new angiotensin-converting enzyme 2 inhibitor in soybean. Biomed. Res., Vol 36, 2015, pp 219-224.
K. Higuchi, S. Watanabe, M. Takahashi, S. Kawasaki, H. Nakanishi, N. K. NishizawaS. Mori Nicotianamine synthase gene expression differs in barley and rice under Fe-deficient conditions. Plant J., Vol 25, 2001, pp 159-167.
D. Mizuno, K. Higuchi, T. Sakamoto, H. Nakanishi, S. MoriN. K. Nishizawa Three nicotianamine synthase genes isolated from maize are differentially regulated by iron nutritional status. Plant Physiol., Vol 132, 2003, pp 1989-1997.
S. Kim, M. Takahashi, K. Higuchi, K. Tsunoda, H. Nakanishi, E. Yoshimura, S. MoriN. K. Nishizawa Increased nicotianamine biosynthesis confers enhanced tolerance of high levels of metals, in particular nickel, to plants. Plant Cell Physiol., Vol 46, 2005, pp 1809-1818.
A. HayashiK. Kimoto Nicotianamine preferentially inhibits angiotensin I-converting enzyme. J Nutr Sci Vitaminol, Vol 53, 2007, pp 331-336.
M. Hayakari, K. Satoh, H. Izumi, T. Kudoh, J. Asano, T. YamazakiS. Tsuchida Kinetic-controlled hydrolysis of Leu-Val-Val-hemorphin-7 catalyzed by angiotensin-converting enzyme from rat brain. Peptides, Vol 24, 2003, pp 1075-1082
M. Hayakari, R. Seito, A. Furugori, Y. HashimotoS. Murakami An improved colorimetric assay of angiotensin-converting enzyme in serum. Clin. Chem. Acta, Vol 144, 1984, pp 71-75.
S. Fushiya, S. Nakatsuyama, Y. SatoS. Nozoe Synthesis of nicotianamine and a related compound, rerivatives of azetidine-2-carboxylic acid. Heterocycles, Vol 15, 1981, pp 819-822.
Y. Ohfune, M. TomitaK. Nomoto Total synthesis of 2’-deoxymugineic acid, the metal chelator excreted from wheat root. J. Am. Chem. Soc., Vol 103, 1981, pp 2409-2410.
F. Matsuura, Y. HamadaT. Shioiri Total synthesis of 2'-deoxymugineic acid and nicotianamine. Tetrahedron, Vol 50, 1994, pp 9457-9470.
K. Miyakoshi, J. OshitaT. Kitahara Expeditious synthesis of nicotianamine and 2'-deoxymugineic acid. Tetrahedron, Vol 57, 2001, pp 3355-3360.
M. Bouazaoui, S. Mari, P. Czernic, C. Curie, J. MartinezF. Cavelier Synthesis and biological activity of nicotianamine and analogues. Adv. Exp. Med. Biol., Vol 611, 2009, pp 555-557.
G. Jones, P. WillettR. C. Glen Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. J. Mol. Biol., Vol 245, 1995, pp 43-53.
G. Jones, P. Willett, R. C. Glen, A. R. LeachR. Taylor Development and validation of fa genetic algorithm for flexible docking. J. Mol. Biol., Vol 267, 1997, pp 727-748.
N. S. Pagadala, K. SyedJ. Tuszynski Software for molecular docking; a review. Biophys. Rev., Vol 9, 2017, pp 91-102.
N. A. Roberts, J. A. Martin, D. Kinchington, A. V. Broadhurst, J. C. Craig, I. B. Duncan, S. A. Galpin, B. K. Handa, J. KayA. Kröhn Rational design of peptide-based HIV proteinase inhibitors. Science, Vol 248, 1990, pp 358-361.
O. M. Becker, D. S. Dhanoa, Y. Marantz, D. Chen, S. Shacham, S. Cheruku, A. Heifetz, P. Mohanty, M. Fichman, A. Sharadendu, R. Nudelman, M. KauffmanS. Noiman An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression. J. Med. Chem., Vol 49, 2006, pp 3116-3135.
K. K. Reddy, S. K. Singh, S. K. TripathiC. Selvaraj Identification of potential HIV-1 integrase strand transfer inhibitors; in silico virtual screening and QM/MM docking studies. . SAR QSAR Environ. Res., Vol 24, 2013, pp 581-595.
C. A. Hunter MELDORA LECTURE. The role fo aromatic interactions in molecular recognition. Chem. Soc. Rev., Vol 23, 1994, pp 101-109.
T. Böttcher, M. Pitscheider S. A. Sieber Natural products and their biological targets; proteomic and metabolomic labeling strategies. Angew. Chem. Int. Ed., Vol 49, 2010, pp 2680-2698.
S. Sato, A. Murata, T. Shirakawa M. Uesugi Biochemical target isolation for novices; affinity-based strategies. Chem. Biol., Vol 17, 2010, pp 616-623.
F. Kotzyba-Hibert, I. KapferM. Goeldner Recent trends in photoaffinitylabeling. Angew. Chem. Int. Ed. Engl., Vol 34, 1995, pp 1296-1312.
M. Hashimoto Y. Hatanaka Recent progress in dazirine-based photoaffinity labeling. Eur. J. Org. Chem., Vol 2008, 2008, pp 2513-2523.
Science Publishing Group
1 Rockefeller Plaza,
10th and 11th Floors,
New York, NY 10020
Tel: (001)347-983-5186