&lt;i&gt;In-silico&lt;/i&gt; studies of HMG-Co A reductase inhibitors present in fruits of &lt;i&gt;Withania coagulans&lt;/i&gt; Dunal (Solanaceae)

Lateef, Tooba; Naeem, Sadaf; Qureshi, Shamim A.

doi:10.4314/tjpr.v19i2.13

Cited by 4 publications

(11 citation statements)

References 19 publications

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“…More specifically, the binding site is surrounded by key residues Arg590, Ser661, Val683, Ser684, Asp690, Lys691 from one subunit and Glu559, Cys561, Leu562, Ala564, Ser565, His752, Lys735, Asn755, Leu853, Ala856 from the another subunit (Shiuan et al 2015). Residues Tyr479, Asp767, and His866, also contribute to the catalytic process (Lateef et al 2020).…”

Section: Molecular Dockingmentioning

confidence: 99%

Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme by dipeptides identified in dry-cured ham

Heres

Mora

2021

Food Prod Process and Nutr

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High cholesterolemia is a key risk factor for the development of cardiovascular diseases, which are the main cause of mortality in developed countries. Most therapies are focused on the modulation of its biosynthesis through 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR) inhibitors. In this sense, food-derived bioactive peptides might act as promising health alternatives through their ability to interact with crucial enzymes involved in metabolic pathways, avoiding the adverse effects of synthetic drugs. Dry-cured ham has been widely described as an important source of naturally-generated bioactive peptides exerting ACEI-inhibitory activity, antioxidant activity, and anti-inflammatory activity between others. Based on these findings, the aim of this work was to assess, for the first time, the in vitro inhibitory activity of HMG-CoAR exerted by dipeptides generated during the manufacturing of dry-cured ham, previously described with relevant roles on other bioactivities.The in vitro inhibitory activity of the dipeptides was assessed by measuring the substrate consumption rate of the 3-hydroxy-3-methylglutaryl CoA reductase in their presence, with the following pertinent calculations.Further research was carried out to estimate the possible interactions of the most bioactive dipeptides with the enzyme by performing in silico analysis consisting of molecular docking approaches.Main findings showed DA, DD, EE, ES, and LL dipeptides as main HMG-CoAR inhibitors. Additionally, computational analysis indicated statin-like interactions of the dipeptides with HMG-CoAR.This study reveals, for the first time, the hypocholesterolemic potential of dry-cured ham-derived dipeptides and, at the same time, converges in the same vein as many reports that experimentally argue the cardiovascular benefits of dry-cured ham consumption due to its bioactive peptide content.

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Section: Molecular Dockingmentioning

confidence: 99%

Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme by dipeptides identified in dry-cured ham

Heres

Mora

2021

Food Prod Process and Nutr

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Section: Resultsmentioning

confidence: 99%

“…We started in silico studies by selecting both lovastatin and its activated form (LHA) as known HMGCR inhibitors (Table 2). In the past, similar studies have also been performed on phytochemical compounds present in extracts of Withania coagulans fruits [68,69]. Molecular docking studies on HMGCR were performed with the aim of analyzing the binding properties of the identified compounds in PHE (Table 1, Figure 1) and hypothesizing the binding site with the AAs involved.…”

Section: Triterpenoic Acids Of Phe Modulate Hmgcr Activity Assuming Similar Poses To Lhe In the Active Site Of The Enzymementioning

confidence: 99%

Bioactive Triterpenes of Protium heptaphyllum Gum Resin Extract Display Cholesterol-Lowering Potential

Mannino

Iovino²,

Lauria

et al. 2021

IJMS

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Hypercholesterolemia is one of the major causes of cardiovascular disease, the risk of which is further increased if other forms of dyslipidemia occur. Current therapeutic strategies include changes in lifestyle coupled with drug administration. Statins represent the most common therapeutic approach, but they may be insufficient due to the onset of resistance mechanisms and side effects. Consequently, patients with mild hypercholesterolemia prefer the use of food supplements since these are perceived to be safer. Here, we investigate the phytochemical profile and cholesterol-lowering potential of Protium heptaphyllum gum resin extract (PHE). Chemical characterization via HPLC-APCI-HRMS2 and GC-FID/MS identified 13 compounds mainly belonging to ursane, oleanane, and tirucallane groups. Studies on human hepatocytes have revealed how PHE is able to reduce cholesterol production and regulate the expression of proteins involved in its metabolism. (HMGCR, PCSK9, LDLR, FXR, IDOL, and PPAR). Moreover, measuring the inhibitory activity of PHE against HMGR, moderate inhibition was recorded. Finally, molecular docking studies identified acidic tetra- and pentacyclic triterpenoids as the main compounds responsible for this action. In conclusion, our study demonstrates how PHE may be a useful alternative to contrast hypercholesterolemia, highlighting its potential as a sustainable multitarget natural extract for the nutraceutical industry that is rapidly gaining acceptance as a source of health-promoting compounds.

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“…Since the last few decades, the whole plants, fruit, and roots of Withania coagulans Dunal (family: Solanaceae) have attracted attention due to their antidiabetic effects in animal models and human pilot trials. ,− The fruit of W. coagulans contains a wide range of bioactive phytoconstituents with varying polarity, solubility, and chemical and physical characteristics.…”

Section: Introductionmentioning

confidence: 99%

“…W. coagulans has been reported to have antifungal, emetic, antibacterial, anti-asthmatic, anti-inflammatory, diuretic, antimicrobial, anti-inflammatory, antitumor, hepato-protective, antihyperglycemic, antihyperlipidemic, anti-atherosclerotic, cardiovascular, immunosuppressive, free radical scavenging, and CNS depressant properties in the scientific literature. − Interestingly, a number of various withanolides, including withaferin A, withanolide A, withanone, coagulin L, coagulanolide, ergostadiene, and sitosterol, were reported. ,− According to phytochemical research, esterases, free amino acids, fatty oils, essential oils, and withanolides are the primary phytoconstituents of the fruit. − The major phytoconstituents in W. coagulans fruit are withanolides, which are steroidal lactones with an ergostane skeleton. − Therefore, the present study’s objective was to investigate and characterize the various compounds of W.…”

Section: Introductionmentioning

confidence: 99%

In Silico Characterization of Withania coagulans Bioactive Compounds as Potential Inhibitors of Hydroxymethylglutaryl (HMG-CoA) Reductase of Mus musculus

Azmi

Khan

Asif³

et al. 2023

ACS Omega

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Hypercholesterolemia is a mediator for the etiology of cardiovascular diseases, which are characterized as the global leading cause of mortality. We aimed to investigate the inhibitory activity of Withania coagulans compounds against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) of Mus musculus using an extensive in silico approach. The 3D structure of the Hmgcr protein is not yet known, so we performed the homology modeling using MODELLER and SWISS-MODEL tools, followed with structural validation and assessment. The PROCHECK web server showed that the top-ranked homology model from SWISS-MODEL has 93.4% of residues in the most-favorable region, the quality factor was 98%, and the Verify3D score was 91.43%, compared to the other generated models. The druggable protein-binding cavities in a 3D model of Hmgcr were investigated with the aid of commonly prescribed statin compounds using the CB-dock approach. We compiled a 3D compound library of W. coagulans, followed by drug-likeness evaluation, and found 20 eligible compounds. The pattern of consensus residues obtained from the CB-dock procedure was then used for grid-box docking of W. coagulans compounds and statin drugs using AutoDock 4.2, respectively. The results showed that withanolide R (−10.77 kcal/mol), withanolide Q (−10.56 kcal/mol), withanolide J (−10.52 kcal/mol), atorvastatin (−8.99 kcal/mol), simvastatin (−8.66 kcal/mol), and rosuvastatin (−8.58 kcal/mol) were promising candidates that bind Hmgcr protein. The key residues involved in protein–ligand (withanolide R) interactions were Y516, C526, V529, I530, M533, I535, and V537, and the formation of a H-bond was at C526, M533, and I535 residues. M533 was the consensus residue having a tendency to form a H-bond with withanolide Q, too. Molecular dynamics simulations were used to validate the top-ranked docked complexes for the stability of the modeled protein. We also predicted the pharmacokinetic properties of binding affinity-based top-ranked compounds and concluded that they could be used as potential inhibitors of Hmgcr. However, further in vitro and in vivo studies are essential to completing the drug development process.

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<i>In-silico</i> studies of HMG-Co A reductase inhibitors present in fruits of <i>Withania coagulans</i> Dunal (Solanaceae)

Cited by 4 publications

References 19 publications

Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme by dipeptides identified in dry-cured ham

Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme by dipeptides identified in dry-cured ham

Bioactive Triterpenes of Protium heptaphyllum Gum Resin Extract Display Cholesterol-Lowering Potential

In Silico Characterization of Withania coagulans Bioactive Compounds as Potential Inhibitors of Hydroxymethylglutaryl (HMG-CoA) Reductase of Mus musculus

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