The lactotripeptides isoleucine-proline-proline and valine-proline-proline do not inhibit the N-terminal or C-terminal angiotensin converting enzyme active sites in humans

Background: Hypertension is the chronic medical condition and it affected billions of people worldwide. Natural medicines are the main alternatives to treatment for a majority of people suffering from hypertension. Niazicin-A, Niazimin-A, and Niaziminin-B compounds from Moringa oleifera ethanolic leave extract were reported to have potent antihypertensive activity. Objective: These compounds were targeted with Angiotensin-converting enzyme [ACE] which is one of the main regulatory enzymes of the renin-angiotensin system. Methods: Protein-ligand docking of these compounds with [ACE] [both domain N and C] was conceded out through Autodock vina and visualization was done by chimera. Pharmacokinetics study of these compounds was predicted by ADME-Toxicity Prediction. Results: Niazicin-A, Niazimin-A, and Niaziminin-B showed high binding affinity with ACE and partially blocked the active sites of the enzyme. Niazicin-A, Niazimin-A and Niaziminin-B showed the estimated free binding energy of -7.6kcal/mol kcal/mol, -8.8kcal/mol and -8.0kcal/mol respectively with C-domain of ACE and -7.9kcal/mol, -8.5kcal/mol and -7.7kcal/mol respectively with N-domain of ACE. The compounds showed better binding energy with angiotensinconverting enzyme in comparison to Captopril -5.5kcal/mol and -5.6kcal/mol and Enalapril [standard] -8.4kcal/mol and -7.5kcal/mol with C and N domain, respectively. Conclusion: Computationally, the selected bioactive molecules have shown better binding energy to known standard drugs which have been already known for inhibition of ACE and can further act as a pharmacophore for in vitro and in vivo studies in the development of alternative medicine.

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POTENSI SENYAWA BIOAKTIF TANAMAN KELOR PENGHAMBAT INTERAKSI ANGIOTENSIN-CONVERTING ENZYME 2 PADA SINDROMA SARS-COV-2

Jurnal Bioteknologi & Biosains Indonesia (JBBI) ◽

10.29122/jbbi.v7i2.4156 ◽

2020 ◽

Vol 7 (2) ◽

pp. 259-270

Author(s):

Maharani Pertiwi Koentjoro ◽

Adyan Donastin ◽

Endry Nugroho Prasetyo

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Protein Data Bank ◽

Active Sites ◽

Moringa Oleifera ◽

Data Bank ◽

Converting Enzyme ◽

Ligand Complex ◽

Angiotensin Converting Enzyme 2 ◽

Pubchem Database

The Potential of Moringa oleifera Bioactive Compounds for Inhibiting Angiotensin-Converting Enzyme 2 Interaction in SARS-Cov-2 Syndrome Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease (COVID-19) is a threat to human health. This infection is determined by the interaction of the spike S1 domain protein with angiotensin-converting enzyme 2 (ACE2) in the epithelial cells of the respiratory tract, especially the lungs. ACE2 inhibition is an important target in controlling COVID-19. Flavonoids of medicinal plants, are known to interfere with ACE (ACE2 homologous). Therefore, this study aims to explore the ability of apiin, epicatechin, and hesperetin from Moringa oleifera in interacting with the ACE2 using MOE 2008.10. The ligand molecules were prepared from PubChem database. The ACE2 protein was retrieved from Protein Data Bank (ID 1R4L) and analyzed for the active sites. Analysis of docking scores and hydrogen bonds of ACE2-ligand complex and active site showed that the affinity of flavonoids can be ranked as hesperetin > epicatechin > apiin > C19H23Cl2N3O4. The results provided computational information that apiin, epicatechin, and hesperetin have the potential to prevent COVID-19 infection. The prediction of activity spectra for substances (PASS) score showed the ligand displays antiviral activity. Infeksi severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pada pandemi coronavirus disease 2019 (COVID-19) menjadi ancaman dunia kesehatan saat ini. Infeksi SARS-CoV-2 ditentukan oleh interaksi protein spike envelope S1 domain dengan reseptor angiotensin-converting enzyme 2 (ACE2) yang diekspresikan pada sel epitel saluran pernafasan terutama paru-paru. Mekanisme penghambatan ACE2 menjadi target penting dalam pengendalian COVID-19. Senyawa bioaktif tanaman obat, seperti flavonoid diketahui mampu mengganggu fungsi banyak makromolekul termasuk ACE (homolog dengan ACE2). Penelitian ini bertujuan mengeksplorasi kemampuan senyawa apiin, epicatechin, dan hesperetin dari Moringa oleifera dalam berinteraksi dengan sisi aktif ACE2 menggunakan metode penambatan molekul. Studi dilakukan dengan preparasi struktur molekul ligan dari PubChem database dan diolah dengan MOE 2008.10. Selanjutnya, data protein ACE2 (Protein Data Bank ID 1R4L) dianalisis sisi aktifnya untuk mengetahui lokasi penambatan ligan senyawa. Analisis skor docking dan ikatan hydrogen komplek ligan dan sisi aktif ACE2 menunjukkan bahwa afinitas flavonoid dapat diperingkatkan sebagai afinitas hesperetin > epicatechin > apiin > C19H23Cl2N3O4. Ketiga ligan senyawa yang terkandung dalam M. oleifera secara in silico mampu mengikat sisi aktif ACE2, sehingga berpotensi mencegah infeksi COVID-19. Skor PASS (prediction of activity spectra for substances) menunjukkan aktivitas biologis ligan yang menyerupai antiviral.

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Structural studies through 1H NMR spectroscopy of somatic angiotensin converting enzyme (ACE) active sites and comparison with testis ACE crystal structure

Collection Symposium Series ◽

10.1135/css200306029 ◽

2003 ◽

Author(s):

Athanassios S. Galanis ◽

Georgios A. Spyroulias ◽

Roberta Pierattelli ◽

Andreas Tzakos ◽

Anastassios Troganis ◽

...

Keyword(s):

Crystal Structure ◽

Nmr Spectroscopy ◽

Angiotensin Converting Enzyme ◽

1H Nmr ◽

1H Nmr Spectroscopy ◽

Active Sites ◽

Structural Studies ◽

Converting Enzyme

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Altered angiotensin-converting enzyme in lung and extrapulmonary tissues of hypoxia-adapted rats

Journal of Applied Physiology ◽

10.1152/jappl.1988.65.1.218 ◽

1988 ◽

Vol 65 (1) ◽

pp. 218-227 ◽

Cited By ~ 21

Author(s):

S. Oparil ◽

A. J. Narkates ◽

R. M. Jackson ◽

H. S. Ann

Keyword(s):

Angiotensin Converting Enzyme ◽

Active Sites ◽

Chronic Hypoxia ◽

Plasma Renin ◽

Ang Ii ◽

Converting Enzyme ◽

Hypoxia Exposure ◽

Catalytically Active ◽

Tissue Homogenates ◽

Ace Activity

The effects of exposing rats to hypoxia (10% O2) at normal atmospheric pressure for periods of 14 or 28 days on angiotensin-converting enzyme (ACE) activity and stores of angiotensin I (ANG I) and angiotensin II (ANG II) in lung, kidney, brain, and testis were examined. ACE activity was measured by spectrophotometric assay, and active sites of ACE were estimated by measuring the binding of 125I-351A [N-(1-carbonyl-3-phenyl-propyl)-L-lysyl-L-proline], a highly specific active site-directed inhibitor of ACE, to tissue homogenates and perfused lungs. Hypoxia exposure produced progressive reductions in ACE activity in lung homogenates and in ACE inhibitor binding to perfused lungs. ANG II levels in lungs from hypoxia-adapted animals were significantly less than air controls, suggesting that the reduction in intrapulmonary ACE activity was associated with reduced local generation of ANG II. ACE activity was increased in kidney and unchanged in brain and testis of hypoxia-adapted rats compared with air controls. Thus the effects of chronic hypoxia on catalytically active ACE and ACE active sites in the intact animal were organ specific. Adaptation to chronic hypoxia did not significantly alter plasma renin activity or ANG I or ANG II levels or serum ACE content. The hypoxia-induced alterations in lung and kidney ACE were reversible after return to a normoxic environment.

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Evidence for the negative cooperativity of the two active sites within bovine somatic angiotensin-converting enzyme

FEBS Letters ◽

10.1016/s0014-5793(03)00825-1 ◽

2003 ◽

Vol 550 (1-3) ◽

pp. 84-88 ◽

Cited By ~ 36

Author(s):

Peter V Binevski ◽

Elena A Sizova ◽

Vladimir F Pozdnev ◽

Olga A Kost

Keyword(s):

Angiotensin Converting Enzyme ◽

Active Sites ◽

Negative Cooperativity ◽

Converting Enzyme

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Characterization of the first non-insect invertebrate functional angiotensin-converting enzyme (ACE): leech TtACE resembles the N-domain of mammalian ACE

Biochemical Journal ◽

10.1042/bj20040522 ◽

2004 ◽

Vol 382 (2) ◽

pp. 565-573 ◽

Cited By ~ 15

Author(s):

Guillaume RIVIÈRE ◽

Annie MICHAUD ◽

Laurence DELOFFRE ◽

Franck VANDENBULCKE ◽

Angélique LEVOYE ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Active Site ◽

Active Sites ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Inhibitory Effect ◽

Converting Enzyme ◽

Ovary Cells

Angiotensin-converting enzyme (ACE) is a zinc metallopeptidase that plays a major role in blood homoeostasis and reproduction in mammals. In vertebrates, both transmembrane and soluble ACE, containing one or two homologous active sites, have been characterized. So far, several ACEs from invertebrates have been cloned, but only in insects. They are soluble and display a single active site. Using biochemical procedures, an ACE-like activity was detected in our model, the leech, Theromyzon tessulatum. Annelida is the most distant phylum in which an ACE activity has been observed. To gain more insight into the leech enzyme, we have developed a PCR approach to characterize its mRNA. The approx. 2 kb cDNA has been predicted to encode a 616-amino-acid soluble enzyme containing a single active site, named TtACE (T. tessulatum ACE). Surprisingly, its primary sequence shows greater similarity to vertebrates than to invertebrates. Stable in vitro expression of TtACE in transfected Chinese-hamster ovary cells revealed that the leech enzyme is a functional metalloprotease. As in mammals, this 79 kDa glycosylated enzyme functions as a dipeptidyl carboxypeptidase capable of hydrolysing angiotensin I to angiotensin II. However, a weak chloride inhibitory effect and acetylated N-acetyl-SDKP (Ac SDAcKP) hydrolysis reveal that TtACE activity resembles that of the N-domain of mammalian ACE. In situ hybridization shows that its cellular distribution is restricted to epithelial midgut cells. Although the precise roles and endogenous substrates of TtACE remain to be identified, characterization of this ancestral peptidase will help to clarify its physiological roles in non-insect invertebrate species.

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