Potent Angiotensin Converting Enzyme Inhibitor Research Articles

Computational assessment of targeting angiotensin-converting enzyme for hypertension management: A structure-based virtual screening approach

Background: Hypertension is a growing public health concern globally. The angiotensin-converting enzyme (ACE) is an enzyme that cleaves the carboxy-terminal His-Leu dipeptide from angiotensin I, yielding the potent vasopressor octapeptide, angiotensin II. ACE inhibitors are a primary treatment option for hypertension, heart failure, and myocardial infarction. However, the use of synthetic ACE inhibitors has been linked to a number of side effects. Therefore, the development of novel and safe ACE inhibitors is a need of time.Methods: This study used a computational screening of a library of known compounds with anti-inflammatory activities against the active site of ACE using the PyRx-Python 0.8 tool to find more potent ACE inhibitors with less or no side effects. The physicochemical properties of the anti-inflammatory compounds were obtained from the Life Chemicals website.Result: The five hits, specifically F3398-2114, F0193-0245, F0163-0089, F0193-0237, and F0302-0060, exhibited notable interactions within the ACE binding pocket and demonstrated greater binding energy compared to the control compound, Lisinopril. All of these compounds displayed favorable physicochemical characteristics and aligned to Lipinski's rule.Conclusion: The compounds F3398-2114, F0193-0245, F0163-0089, F0193-0237, and F0302-0060 have the potential to be used as ACE inhibitors; however, further experimental validation is required to optimize them as ACE inhibitors.Keywords: Hypertension; Angiotensin-converting enzyme; Heart failure; Lipinski's rule

Antioxidant and Angiotensin-Converting Enzyme Inhibitory Activity of Faba Bean-Derived Peptides After In Vitro Gastrointestinal Digestion: Insight into Their Mechanism of Action.

Faba bean flour, after in vitro gastrointestinal digestion, showed important antioxidant and angiotensin-converting enzyme (ACE) inhibitory activities. In the present study, 11 faba bean- derived peptides were synthesized to confirm their bioactivities and provide a deeper understanding of their mechanisms of action. The results revealed that 7 peptides were potent antioxidants, namely, NYDEGSEPR, TETWNPNHPEL, TETWNPNHPE, VIPTEPPH, VIPTEPPHA, VVIPTEPPHA, and VVIPTEPPH. Among them, TETWNPNHPEL had the highest activity in the ABTS (EC50 = 0.5 ± 0.2 mM) and DPPH (EC50 = 2.1 ± 0.1 mM) assays (p < 0.05), whereas TETWNPNHPE had the highest activity (p < 0.05) in the ORAC assay (2.84 ± 0.08 mM Trolox equivalent/mM). Synergistic and/or additive effects were found when selected peptides (TETWNPNHPEL, NYDEGSEPR, and VVIPTEPPHA) were combined. Four peptides were potent ACE inhibitors, where VVIPTEPPH (IC50 = 43 ± 1 μM) and VVIPTEPPHA (IC50 = 50 ± 5 μM) had the highest activity (p < 0.05), followed by VIPTEPPH (IC50 = 90 ± 10 μM) and then VIPTEPPHA (IC50 = 123 ± 5 μM) (p < 0.05). These peptides were noncompetitive inhibitors, as supported by kinetic studies and a molecular docking investigation. This study demonstrated that peptides derived from faba beans have multifunctional bioactivities, making them a promising food-functional and nutraceutical ingredient.

Discovery of Potent Angiotensin-Converting Enzyme Inhibitors in Pomegranate as a Treatment for Hypertension.

Pomegranate (Punica granatum L.) is associated with numerous health benefits due to its high levels of antioxidant polyphenolic substances. Since pomegranate extract has been shown to inhibit angiotensin-converting enzyme (ACE), the potential inhibitory effect of most of its main constituents against ACE is unknown. Therefore, we tested the activities of 24 major compounds, the majority of which significantly inhibited ACE. Notably, pedunculagin, punicalin, and gallagic acid were the most effective ACE inhibitors with IC50 values of 0.91, 1.12, and 1.77 μM, respectively. As demonstrated in molecular docking studies, compounds block ACE by forming multiple hydrogen bonds and hydrophobic interactions with catalytic residues and zinc ions in ACE's C- and N-domains, consequently inhibiting ACE's catalytic activity. Also, the most active pedunculagin stimulated nitric oxide (NO) production, activated the endothelial nitric oxide synthase enzyme (eNOS), and significantly increased eNOS protein expression levels up to 5.3-fold in EA.hy926 cells. Furthermore, pedunculagin increased in cellular calcium (Ca2+) concentration promoted eNOS enzyme activation and reduced the production of reactive oxygen species (ROS). In addition, the active compounds improved glucose uptake in insulin-resistant C2C12 skeletal muscle cells in a dose-dependent manner. The results of these computational, in vitro, and cellular experiments provide further evidence to the traditional medicine that involves using pomegranates to treat cardiovascular diseases like hypertension.

Determination of perindopril erbumine by oxidative coupling reaction using 2, 6-dichloroquinone-4-chlorimide

Perindopril erbumine (Perindopril tert-butylamine salt) is a potent angiotensin-converting enzyme (ACE) inhibitor. It is used to treat the patients with hypertension and heart failure problems. A sensitive, inexpensive and precise analytical technique has been developed for the estimation of perindopril in bulk and formulations. The procedure involves the development of colour by forming an oxidative coupling reaction between drug (PPE) and reagent such as 2, 6-dichloroquinone-4-chlorimide (DCQC). The formed colored species were measured at (max=520 nm. The developed method showed linearity within the concentration limits of 25-75 μg mL-1. The linear correlation coefficient (r) and molar absorptivity were found to be 0.9999 and 3.285 x 103 mol-1cm-1. % Recovery ± SD values were in the range of 99.69 - 100.51 (+ 0.42 - ( 0.41) (n=3) which indicates the accuracy of the developed method. The interference of other excipients that are commonly present in formulations is found to be negligible. Precision and accuracy of the proposed method were confirmed by student t-test and F-tests at 95% confidence limits with (n-1) degrees of freedom. The validity parameters of proposed method were calculated by ICH guidelines.

Use of convertible isocyanides for the synthesis of benazepril hydrochloride

Herein, we have described a novel and concise synthesis of the potent angiotensin-converting enzyme (ACE) inhibitor, benazepril hydrochloride (7) in trifluoroethanol via an Ugi three-component reaction in shorter reaction times. The key step is the trifluoroacetic acid-mediated hydrolysis of secondary amides (4a and 4b) followed by esterification as a domino process to form corresponding ethyl ester (6). Mainly two universal convertible isocyanides (1a and 1b) were used for the synthesis of benazepril hydrochloride. Synopsis: An efficient synthesis of benazepril hydrochloride using Ugi three-component reaction.

Synthesis, crystal structure, molecular docking studies and biological evaluation of aryl substituted dihydroisoquinoline imines as a potent angiotensin converting enzyme inhibitor

The different functionalities of imine group found in many compounds are of important biological activity. Since, the development of novel imines is biologically encouraged, this study aims to develop a straightforward synthesis pathway of dihydroisoquinoline imines that could reveal antihypertensive effects. Starting from 2-méthyl-1-phényl-2-propanol, four different dihydroisoquinoline imines compounds (2a-d) were obtained and their structures were analyzed by mass spectrum, elemental analysis and NMR spectral studies. The crystal structure of 2b was determined from single crystal X-ray diffraction data.The newly synthesized compounds were evaluated for angiotensin I-converting enzyme (ACE) inhibition, using an enzymatic in vitro assay. The results were compared to Captopril as a reference drug. Compounds 2a, 2b and 2d showed inhibition activity with IC50 values of 0.15, 0.13 and 0.40 mg/ml, respectively. The docking of chemical compounds in the ACE active site explained the higher inhibitory capability of compounds 2a and 2b on the catalytic activity of the enzyme, indicating a potential anti-hypertensive effect of these compounds.

QSAR studies of angiotensin converting enzyme inhibitors using CoMFA, CoMSIA and molecular docking

In order to better understand the biochemical interactions governing their activities in lowering blood pressure, multiple quantitative structure-activity relationship (QSAR) models were developed from a data set of 58 angiotensin converting enzyme (ACE) inhibitors. The models were built by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The best CoMFA model had a cross-validation q2 value of 0.940, a non cross-validation r2 value of 0.952 and an external validation statistic Qext 2 value of 0.920. For the best CoMSIA model the values were with q2 = 0.872, r2 = 0.926 and Qext 2 = 0.868. Based on the contour maps, eight new ACE inhibitors were designed. Molecular docking was employed to further explore the binding requirements between the ligands and the receptor protein which included several hydrogen bonds between the ACE inhibitors and active site residues. This study showed extensive interactions between ACE inhibitors and residues of HIS383, GLU384, HIS513, TYR520 and LYS511 in the active site of ACE. The design of potent new inhibitors of ACE can get useful insights from these results.

Southeast Asian Medicinal Plants with Angiotensin Converting Enzyme (ACE) Inhibition Properties

Introduction: This article aims to provide a summary of medicinal plants in the Southeast Asian countries that have an angiotensin-converting enzyme (ACE) inhibitory activity that is therapeutically useful for treating hypertension. Methods: This review paper is a result of extensive searches via electronic database platforms, including Pubmed, Google Scholar, Scopus, and Science Direct with the keyword search terms: ACE enzyme, Southeast Asia countries, plants, and extracts. Results: Thirty-four articles on ACE inhibition activity of 76 Southeast Asian medicinal plants were found and further reviewed. Several plants from Malaysia (Chassalia curviflora, Citrus hystrix, Murraya koenigii, Senna garrettiana), Indonesia (Gnetum Gnemon, Momordica charantia, Nasturtium officinale, Peperomia pellucida, Pereskia saccharose), and Thailand (Mammea siamensis) were found to exhibit strong ACE inhibitory activity in vitro. Bioactive compounds such as 3’,4’, dihydroxy-3-5 dimethoxy flavone-7-O-β-rhamnose and quercetin-3-O-glucoside showed the highest potency in exhibiting the ACE inhibition activity in this review. Conclusions: This review suggests for an in-depth investigation on the potent crude extracts for the potential development of complementary herbal medicines as well as on the potent ACE inhibitor compounds for further development as new ACE inhibitor candidates for hypertension therapy.

Identification of antihypertensive peptides from mung bean protein hydrolysate and their effects in spontaneously hypertensive rats

Defatted mung bean meal was hydrolyzed with bromelain to obtain MPH, which was fractionated into different peptide fractions (<1 kDa, 1–5 kDa, 5–10 kDa, >10 kDa) using membrane ultrafiltration. The <1 kDa was the most active inhibitor of angiotensin converting enzyme (ACE) and renin. Five peptides (LPRL, YADLVE, LRLESF, HLNVVHEN, and PGSGCAGTDL) identified from the <1 kDa fraction were studied for antihypertensive effects in comparison to the MPH. Results showed that LRLESF was the most potent inhibitor of ACE (IC50 = 5.4 µM) while LPRL was the weakest (IC50 = 1912 µM). In contrast, YADLVE was the strongest renin inhibitor with 97% inhibition while LRLESF was the weakest (~30%). Oral administration to spontaneously hypertensive rats revealed strong blood pressure reductions with up to −36 mmHg when compared to −15 mmHg for MPH. However, YADLVE had the most persistent effect after 24 h while PGSGCAGTDL had the least.

Antioxidant, Hypolipidemic and Angiotensin Converting Enzyme Inhibitory Effects of Flavonoid-rich Fraction of Hyphaene thebaica (Doum Palm) Fruits on Fat-fed Obese Wistar Rats

Aims: This study investigated the antioxidant, hypolipidemic and angiotensin converting enzyme (ACE) inhibitory effects of flavonoid-rich fraction of H. thebaica on fat-fed obese wistar rats.&#x0D; Study Design: Twenty-five rats were divided into 5 groups of 5 rats each: Control (standard diet, untreated), Obese control (Fat-fed, untreated), Standard control (Fat-fed, treated with 70 mg/kg Atorvastatin), Groups 4 and 5 (Fat-fed, treated with 100 and 250 mg kg-1 flavonoid-rich fraction, respectively). The rats were given high fat diet to induce obesity, after which treatment was administered for fourteen (14) days, and on the 15th day, rats were sacrificed and blood samples collected.&#x0D; Results: From the results, induction of obesity significantly (P&lt;0.05) increased body weight, some lipoproteins, ACE activity, superoxide dismutase, catalase and glutathione peroxidase levels, while HDL cholesterol and malondialdehyde levels decreased. Treatment of obese rats with the standard drug, atorvastatin and flavonoid-rich fraction of H. thebaica significantly (P&lt;0.05) decreased ACE activity, total cholesterol, triglyceride and LDL cholesterol, while HDL cholesterol and malondialdehyde increased.&#x0D; Conclusion: This study has demonstrated that the flavonoid-rich fraction of H. thebaica is hypolipidemic, possesses antioxidant activities, and may contain potent ACE inhibitors.

Design and evaluation of four novel tripeptides as potent angiotensin converting enzyme (ACE) inhibitors with anti-hypertension activity

The current study investigated the angiotensin-converting enzyme (ACE) inhibitory activity of 4 synthetic tripeptides. All the peptides showed enzyme inhibitory activity, especially two promising ones, TTP (Thea-Thea-Pro) and gAgAP (GABA-GABA-Pro), with IC50 values of 0.92 and 3.4 μmol/L, respectively. Enzyme inhibition kinetics determined by Lineweaver-Burk plots revealed that TTP and gAgAP were competitive inhibitors with Ki values of 0.87 and 3.12 μmol/L, respectively. Molecular docking experiments confirmed that the higher inhibitory potency of TTP and gAgAP might be attributed to the formation of several critical hydrogen bonds with the active site residues in ACE. We further demonstrated that TTP and gAgAP initiated a rapid and significant decrease in systolic blood pressure (SBP) in spontaneously hypertensive rats (SHRs). TTP treatment lowered SBP to the same extent as captopril, although the duration of anti-hypertensive effect was shorter in TTP group than that observed in captopril group. Moreover, the transcription levels of angiotensin II receptor type 1 (agtr1) and miR-132/-212 were downregulated in SHRs after administration of TTP and gAgAP. In particular, TTP treatment caused a comparable reduction of agtr1 levels compared to captopril treatment, while miR-132/212 expression was significantly decreased. These results showed that compound TTP might be served as a potential antihypertensive candidate.

Moringa oleifera leaves methanolic extract inhibits angiotensin converting enzyme activity in vitro which ameliorates hypertension

Angiotensin Converting Enzyme (ACE) regulates blood pressure. ACE converts angiotensin I to angiotensin II which binds with its receptors and through a cascade of reactions constrict blood vesels, consequently results in increased blood pressure, called hypertension. Inhibition of ACE activity is considered as an useful therapeutic target that reduce hypertension. Moringa oleifera leaves have traditionally been used in Ayurvedic medicine for their antihypertensive activity and antihypertensive effect of Moringa leaves was reported on spontaneously hypertensive rats. So, we hypothesize that Moringa oleifera leaves methanolic extract (MOLME) might inhibit ACE activity. Inhibition of ACE activity by MOLME was estimated in vitro. In this study, inhibition of ACE by MOLME was evaluated by spectrophotometric method. MOLME inhibited ACE activity in the substrate hippuryl-L-histidyl-L-leucine (HHL) with an IC50 value of 226.37 μg/ml with a reference compound, captropril (CP), a potent ACE inhibitor with an IC50 value of 0.0289 μM. The mode of ACE inhibition in HHL with or without MOLME revealed that the Vmax (0.0857 and 0.0541 OD/30 min, respectively) was changed and the Km values were 4.671 and 4.41. The results indicate that MOLME acts as a non-competitive inhibitor for ACE. CP was found a competitive inhibitor of ACE. MOLME might be a potential natural inhibitor of ACE which reduces hypertension.

Design, synthesis and biological evaluation of Schiff bases of 4-amino-1,2,4-triazole derivatives as potent angiotensin converting enzyme inhibitors and antioxidant activities

This work reports a novel and highly efficient methodology for the synthesis of Schiff bases of 4-amino-1,2,4-triazole derivatives (3a-h) by the condensation of 4-amino-5-methyl-3-oxo-2-tosyl-1,2,4-triazol-3-one (2) derivative with various aromatic aldehydes under ultrasound irradiation. The major advantages of the reported method are its operational simplicity, extremely mild reaction conditions, short reaction times, and excellent yields. The structures of the synthesized compounds were elucidated by IR, 1H NMR, 13C NMR, elemental analysis, and the X-ray crystallography (for compound 3f).The antioxidant activity of the synthesized compounds was determined by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) method. The IC50 value of synthesized Schiff bases were calculated and compared with standard BHA. All compounds showed excellent activity with inhibition values in the range of 71.22 ± 0.98–96.42 ± 0.02% at 1.20 μM.The newly synthesized compounds were also evaluated for angiotensin I-converting enzyme (ACE) inhibition. The results were compared to captopril as a reference drug. All compounds showed ACE inhibition activity from 66% to 95%. Moreover, the synthetic compounds displayed virtually no cytotoxicity. The docking of chemical compounds in the ACE active site revealed possible inhibitory effect of all compounds on the catalytic activity of the enzyme, which would satisfactorily explain the anti-hypertensive effect of these compounds.

Potent ACE inhibitors from 5-hydroxy indanone derivatives

A novel triazole derivatives(±)-2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b]furan-6(2H)-one (12a–j) were designed and synthesized by the reaction between racemic azide and terminal acetylenes under click chemistry reaction conditions followed by biological evaluation as angiotensin converting enzyme (ACE) inhibitors. β-Amino alcohol derivatives of 1-indanone (15a–l) were synthesized from 5-hydroxy indanone, it was reacted with epichlorohydrin and followed by oxirane ring opening with various piperazine derivatives. Among the newly synthesized compounds 12b (IC50: 1.388024 µM), 12g (IC50: 1.220696 µM), 12j (IC50: 1.312428 µM) and 15k (IC50: 1.349671 µM) and 15l (IC50: 1.330764 µM) emerged as most active non-carboxylic acid ACE inhibitors with minimal toxicity comparable to clinical drug Lisinopril.

Design, synthesis of novel Triazolones and bis-Triazolones derivatives under ultrasound irradiation and evaluation as potent angiotensin converting enzyme (ACE) inhibitors

The condensation of several primary amines and diamines with various N1-ethoxycarbonyles N1-tosylhydrazonates (1a-b), triazolones (2) and bis-triazolone (3) resulted in ethanol under ultrasound irradiation. Compared with the conventional methods, the main advantages of the present procedure are milder conditions, shorter reaction time and higher yields. The newly synthesized compounds were evaluated for angiotensin I-converting enzyme (ACE) inhibition. The results were compared to Captopril as a reference drug. Compounds 3b, 2h, 3a, 2d, and 2f showed not only inhibition activity with IC50 values of 0.162, 0.253, 0.253, 0.281 and 0.382 µM, respectively, but also minimal toxicity. The docking of chemical compounds in the ACE active site showed possible inhibitory effect of all compounds on the catalytic activity of the enzyme, which would satisfactorily explain the anti-hypertensive effect of these compounds.

2D and 3D Qsar Studies on Captropril Derivatives as Potent Angiotensin-Converting Enzyme (ACE) Inhibitors

2D and 3D Qsar Studies on Captropril Derivatives as Potent Angiotensin-Converting Enzyme (ACE) Inhibitors

Discovery of a potent angiotensin converting enzyme inhibitor via virtual screening

Prompted by the prominent role of angiotensin converting enzyme (ACE) in hypertension, heart failures, myocardial infarction and diabetic nephropathy, we have attempted to discover novel ACE inhibitors through ligand-based virtual screening. Molecular docking method and rigorously validated model was utilized to search a natural compounds database. Finally, 36 compounds were randomly selected and subjected to in vitro ACE kinase inhibitory assay using fluorescence assays method. The results showed that three compounds (Licochalcone A, Echinatin and EGCG) have strong potential to be developed as a new class of ACE inhibitors. Further chemical modification via fragment modifications guided by structure and ligand-based computational methodologies can lead to discover better agents as potential clinical candidates.

Angiotensin converting enzyme (ACE) inhibitory peptides derived from the simulated in vitro gastrointestinal digestion of cooked chicken breast

The release of encrypted angiotensin converting enzyme (ACE) inhibitory peptides upon simulated in vitro gastrointestinal (GI) digestion of Korat crossbred (KC) and commercial broiler (BR) breast meat varied with cooking methods. Digestas of KC breast meat heated at 70°C for 0.5h (H-0.5) showed the highest ACE inhibitory activity, while digestas of KC chicken heated at 121°C for 1h showed the lowest inhibitory activity. ACE inhibitory activity varied with the protein digestibility. After a series of chromatographic techniques, we identified KPLLCS, ELFTT, and KPLL, novel potent ACE inhibitor peptides whose sequences were homologous to that of myosin and whose IC50 values were 0.37, 6.35 and 11.98μM, respectively. ELFTT and KPLL were resistant to plasmin hydrolysis for up to 60min. Therefore, KC chicken meat heated at H-0.5 could serve as a source of ACE inhibitory peptides upon GI digestion.

Novel angiotensin-converting enzyme inhibitory peptides from caseins and whey proteins of goat milk

Angiotensin-converting enzyme (ACE) plays a central role in blood pressure regulation by producing the vasoconstrictor angiotensin II. The inhibition of ACE with natural inhibitors, as alternatives to avoid the side effect of synthetic drugs, is a major target in the prevention of hypertension. In this study, we examined the separated caseins and whey proteins of goat milk for the presence of ACE inhibitory peptides. Digestion of isolated whey proteins and caseins of goat milk by gastric pepsin generated soluble hydrolysates exhibiting significant inhibition of ACE compared to weak inhibition by undigested proteins. The hydrolysates were fractionated by size exclusion chromatography, Sephacryl S-100 column, into four fractions (F1–F4). The late-eluting fraction (F4) of either whey or caseins exhibited greater ACE inhibition. Peptides in both F4 fractions, isolated by RP-HPLC, exhibited variable ACE inhibitory activities with the hydrophobic peptide peaks being the most potent ACE inhibitors. MALDI-TOF MS/MS resulted in identification of three potent ACE inhibitory peptides: PEQSLACQCL from β-lactoglobulin (residues 113–122), QSLVYPFTGPI from β-casein (residues 56–66), and ARHPHPHLSFM from κ-casein (residues 96–106). The peptides from whey and caseins exert significant ACE inhibitory activities comparable to that of captopril, an antihypertensive drug, exhibiting IC50 values of 4.45μM and 4.27μM, respectively. The results introduce, for the first time, new potent ACE-inhibitory peptides that can be released by gastric pepsin of goat milk whey and caseins and thus may pave the way for their candidacy as anti-hypertensive bioactive peptides and prevention of associated disorders.

Amadori compounds as potent inhibitors of angiotensin-converting enzyme (ACE) and their effects on anti-ACE activity of bell peppers

The angiotensin-converting enzyme (ACE) inhibitor activity of Amadori compounds (ACs) was evaluated in vitro. The results revealed that the N-(1-deoxy-d-fructose-1-yl) glutamic acid was the most active with the lowest IC50 value (0.2590 mM), followed by N-(1-deoxy-d-fructose-1-yl) histidine (0.5676 mM); others showed weak ACE inhibition. Besides, we further studied the change of AC content and corresponding anti-ACE activity during heating of the bell pepper. The AC content in fresh bell pepper was low and drying of the bell pepper led to a significant increase, especially at the beginning five days, in N-(1-deoxy-d-fructose-1-yl) glutamic acid, N-(1-deoxy-d-fructose-1-yl) histidine and the total of eight ACs respectively from nd (not detected) −5.53, 0.76–6.47 and 11.17–100.01 mg/g; simultaneously, the IC50 values for bell pepper extracts decreased from 0.2161 to 0.04627 mM during thermal processing, showing anti-ACE activity increase, which illustrated that the ACs formed during heating of the bell pepper can contribute to the increase of ACE inhibitory activities.