In-vitro and in-silico determinations of HMG-CoA reductase inhibition potential of caffeic acid for therapeutics of hypercholesterolemia

Abstract Background: The HMG-CoA inhibitor are used to control adverse cardiovascular event caused by Hypercholesterolemia and dyslipidaemia. The current study was aimed to evaluate the ability of phytoconstituents of an aqueous seed extract of Acacia senegal (L.) Willd to inhibit HMG-CoA reductase and regress the formation of atherosclerotic plaque. Methods: The chemical fingerprinting of the test extract was assessed by LC-MS. Consequently, the assessments of in-vitro, in-vivo, and in-silico were performed by following the standard methods.Results: The in-vitro assessment of the test extract revealed 74.1 % inhibition potential of HMG-CoA reductase. In-vivo evaluations of the test extract indicated that treated hypercholesterolemic rabbits exhibited a significant (𝑃 ≤ 0.001) ameliorations in the biomarker indices of the dyslipidaemia, such as the atherogenic index, Castelli risk index (I&II), atherogenic coefficient along with lipid profile. Concomitantly, significant reductions were observed in the atherosclerotic plaque area and antioxidants. The in-silico study of molecular docking shown interactions capabilities of key phytoconstituents of the test extract with target protein of HMG-CoA reductase which further validated by the molecular dynamics through potentail energy, NPT, NVT, RSMD and others. Subsequently, the ADMET analysis shown ideal druggability. Conclusion: The results indicate that phytoconstituents of an aqueous seed extract of Acacia senegal (L.) Willd. could inhibit HMG-CoA reductase and improve the levels of antioxidants activity that may reduce symptoms associated with hypercholesterolemia.

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Molecular rationale delineating the role of lycopene as a potent HMG-CoA reductase inhibitor: in vitro and in silico study

Natural Product Research ◽

10.1080/14786419.2015.1108977 ◽

2015 ◽

Vol 30 (18) ◽

pp. 2111-2114 ◽

Cited By ~ 17

Author(s):

Sahir Sultan Alvi ◽

Danish Iqbal ◽

Saheem Ahmad ◽

M. Salman Khan

Keyword(s):

In Silico ◽

Reductase Inhibitor ◽

Hmg Coa Reductase ◽

In Silico Study ◽

Hmg Coa Reductase Inhibitor ◽

Coa Reductase

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IAF, QGF, and QDF Peptides Exhibit Cholesterol-Lowering Activity through a Statin-like HMG-CoA Reductase Regulation Mechanism: In Silico and In Vitro Approach

International Journal of Molecular Sciences ◽

10.3390/ijms222011067 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11067

Author(s):

Mariana Silva ◽

Biane Philadelpho ◽

Johnnie Santos ◽

Victória Souza ◽

Caio Souza ◽

...

Keyword(s):

In Silico ◽

Synthetic Peptides ◽

Cholesterol Synthesis ◽

Reductase Activity ◽

Regulation Mechanism ◽

Protein Extract ◽

Hmg Coa Reductase ◽

Coa Reductase ◽

Lowering Activity

In this study, in silico approaches are employed to investigate the binding mechanism of peptides derived from cowpea β-vignin and HMG-CoA reductase. With the obtained information, we designed synthetic peptides to evaluate their in vitro enzyme inhibitory activity. In vitro, the total protein extract and <3 kDa fraction, at 5000 µg, support this hypothesis (95% and 90% inhibition of HMG-CoA reductase, respectively). Ile-Ala-Phe, Gln-Gly-Phe, and Gln-Asp-Phe peptides were predicted to bind to the substrate binding site of HMGCR via HMG-CoAR. In silico, it was established that the mechanism of HMG-CoA reductase inhibition largely entailed mimicking the interactions of the decalin ring of simvastatin and via H-bonding; in vitro studies corroborated the predictions, whereby the HMG-CoA reductase activity was decreased by 69%, 77%, and 78%, respectively. Our results suggest that Ile-Ala-Phe, Gln-Gly-Phe, and Gln-Asp-Phe peptides derived from cowpea β-vignin have the potential to lower cholesterol synthesis through a statin-like regulation mechanism.

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Novel Phytoconstituents of an Aqueous Pod Extract of Prosopis Cineraria (L.) Druce Attenuate Atherosclerotic Plaque and Hypercholesterolemia in Rabbits

10.21203/rs.3.rs-56652/v1 ◽

2020 ◽

Author(s):

Heera Ram ◽

Noopur Jaipal ◽

Pramod Kumar ◽

Jaykaran Charan ◽

Priya Kashyap ◽

...

Keyword(s):

Atherosclerotic Plaque ◽

In Silico ◽

Reductase Activity ◽

Hmg Coa Reductase ◽

Prosopis Cineraria ◽

Oral Supplementation ◽

Coa Reductase ◽

Leading Compounds

Abstract Background and objectives: The pod of Prosopis cineraria traditionally used in several ailments and key component of traditional food recipe of the Panchkuta of western Rajasthan, India. The current study was targeted to assess ability of phytoconstituents of aqueous pod extract of Prosopis cineraria to inhibit HMG-CoA reductase activity and regress atherosclerotic plaque were investigated in in-vitro, in-vivo, and in-silico studies. Material and Methods: LCMS, GCMS, and FTIR analysis were used to characterize the phytoconstituents of the test extract. Accordingly, the in-vitro, in-vivo and in-silico assessments were performed by following the standard methods. Results: The phytochemical results shown the presence of cloprostenol, cinecromen, and dirithromycin as leading compounds. Accordingly, in-vivo assay of test extract shown HMG-CoA inhibition activity by 78.1 % (IC50 was 0.03 μg/ml). Hypercholesterolemia was induced in rabbits through oral supplementation of a high fat diet (21 % fat) with cholesterol powder supplementation. Administration of the test extract caused significant (𝑃 ≤ 0.001) improvement in the lipid profile and antioxidant levels in the test rabbits, relative to the hypercholesterolemic control rabbits. Subsequently, the reductions in the atherosclerotic plaque and improvement in lumen volume were pointedly observed in the treated groups. In-silico analyses of molecular docking and ADMET revealed significant interactions and druggability profile. Conclusion: It can be stated that the phytoconstituents of aqueous pod extract of Prosopis cineraria have the capacity to inhibit HMG-CoA reductase and regress the atherosclerotic plaque which may be beneficial to the treatment of hypercholesterolemia.

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Efficacy of Small Molecule Phytochemicals of Petroleum Ether Pod Extract of Prosopis cineraria (L.) Druce on HMG-CoA Reductase and Biomarker Indices of Lipoproteins: In-vitro, In-vivo and In-silico Study

Biointerface Research in Applied Chemistry ◽

10.33263/briac123.29883001 ◽

2021 ◽

Vol 12 (3) ◽

pp. 2988-3001

Keyword(s):

Petroleum Ether ◽

Gallic Acid ◽

Small Molecule ◽

In Silico ◽

Atherogenic Index ◽

Hmg Coa Reductase ◽

Prosopis Cineraria ◽

Coa Reductase

The assigned goals of the study were examined to HMG-CoA reductase inhibition and antioxidants potential of the small molecule phytochemicals of petroleum ether pod extract of Prosopis cineraria (L.) Druce by in-vitro, in-vivo, and in-silico assessments. The phytochemical fingerprinting of the extract was done by LC-MS analysis, and compounds were identified using mass hunter software. In-vitro HMG-CoA reductase assay performed by sigma Aldrich kit. According, in-vivo investigations were conducted by using a hypercholesterolemic rabbit animal model. Further, in-silico analyses of molecular docking and ADMET were conducted by standard protocol. The leading identified compounds, i.e., prosogerin-A, luteolin, and gallic acid, were docked with the target enzyme of HMG-CoA reductase, which demonstrated significant binding energies up to -7.2 to 8.1(Kcal/mol). Subsequently, the ADMET predictions revealed druggability and ideal pharmacokinetics profile. Accordingly, the in-vitro HMG-CoA reductase inhibition assay was showed 53.1% inhibition capability of the test extract. The in-vivo investigation shown that the test extract caused significant reductions in the atherogenic index (log (Total cholesterol/triglyceride), Castelli risk index-I (CRI-I), and Castelli risk -II(CRI-II) along with lipid profile and antioxidants levels. It can be concluded that small-molecule phytochemicals such as Prosogerin A, Luteolin, Gallic acid are present in petroleum ether pod extract of Prosopis cineraria (L.) Druce possesses the capability to subside hypercholesterolemia and ameliorations in biomarker lipoproteins indices through HMG-CoA reductase inhibition and antioxidant potential.

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In vitro antioxidant, antiglycation, and enzymatic inhibitory activity against α-glucosidase, α-amylase, lipase and HMG-CoA reductase of Terminalia boivinii Tul.

Biocatalysis and Agricultural Biotechnology ◽

10.1016/j.bcab.2021.102235 ◽

2021 ◽

pp. 102235

Author(s):

Bongani Sicelo Dlamini ◽

Carlos Eduardo Hernandez ◽

Chiy-Rong Chen ◽

Wen-Ling Shih ◽

Jue-Liang Hsu ◽

...

Keyword(s):

Inhibitory Activity ◽

Hmg Coa Reductase ◽

Coa Reductase

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An autonomous, but INSIG-modulated, role for the Sterol Sensing Domain in mallostery-regulated ERAD of yeast HMG-CoA reductase

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015910 ◽

2020 ◽

pp. jbc.RA120.015910

Author(s):

Margaret A Wangeline ◽

Randolph Y Hampton

Keyword(s):

Binding Site ◽

Quaternary Structure ◽

Limited Proteolysis ◽

Hmg Coa Reductase ◽

Coa Reductase ◽

Level Analysis

HMG-CoA reductase (HMGR) undergoes feedback-regulated degradation as part of sterol pathway control. Degradation of the yeast HMGR isozyme Hmg2 is controlled by the sterol pathway intermediate GGPP, which causes misfolding of Hmg2, leading to degradation by the HRD pathway; we call this process mallostery. We evaluated the role of the Hmg2 sterol sensing domain (SSD) in mallostery, as well as the involvement of the highly conserved INSIG proteins. We show that the Hmg2 SSD is critical for regulated degradation of Hmg2 and required for mallosteric misfolding of GGPP as studied by in vitro limited proteolysis. The Hmg2 SSD functions independently of conserved yeast INSIG proteins, but its function was modulated by INSIG, thus imposing a second layer of control on Hmg2 regulation. Mutant analyses indicated that SSD-mediated mallostery occurred prior to and independent of HRD-dependent ubiquitination. GGPP-dependent misfolding was still extant but occurred at a much slower rate in the absence of a functional SSD, indicating that the SSD facilitates a physiologically useful rate of GGPP response, and implying that the SSD is not a binding site for GGPP. Non-functional SSD mutants allowed us to test the importance of Hmg2 quaternary structure in mallostery: a non-responsive Hmg2 SSD mutant strongly suppressed regulation of a co-expressed, normal Hmg2. Finally, we have found that GGPP-regulated misfolding occurred in detergent-solubilized Hmg2, a feature that will allow next-level analysis of the mechanism of this novel tactic of ligand-regulated misfolding.

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