Effects of ezetimibe on lipids and lipoproteins in patients with hyper­cholesterolemia and different apolipoprotein E genotypes

Márk, László; Dani, Győző; Fazekas, Ozseb; Szüle, Olga; Kovacs, Hajnalka; Katona, András

doi:10.1185/030079907x199817

Cited by 7 publications

(7 citation statements)

References 53 publications

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“…There is only one study concerning the modulating effect of APOE ε2/ε3/ε4 polymorphism during ezetimibe treatment [73]. This open-label study included only 28 patients; no genotyperelated differences were found in the lipid status during the 6-week treatment.…”

Section: Apoe Polymorphisms and The Response During Lipid-lowering Therapymentioning

confidence: 99%

Pharmacogenetics of Apolipoprotein E Gene During Lipid-Lowering Therapy: Lipid Levels and Prevention of Coronary Heart Disease

et al. 2008

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A non-optimal plasma concentration of lipids is among the major modifiable risk factors of atherosclerosis. Therefore, the prevention of cardiovascular disease by means of lipid-lowering therapy with statins and other agents is of great importance for patient groups where a lifestyle change, for example, diet modification, does not lead to adequately reduced lipid levels. The response of low-density-lipoprotein cholesterol (LDL-C) levels to statin therapy is highly variable. This is partly attributed to hereditary variation in genes involved in pharmacokinetics, pharmacodynamics and lipid metabolism. The pharmacogenetics of lipid-lowering therapy have been investigated for more than 40 different genes. The gene for apolipoprotein E (APOE) has been the most frequently studied, particularly regarding the epsilon2/epsilon3/epsilon4 polymorphism. Those with the epsilon4 allele seem to have the poorest and those with the epsilon2 allele the strongest response to statins with regards to LDL-C levels. In addition, the epsilon2 carriers may reach the LDL-C treatment goals more frequently than epsilon4 carriers. Few studies have investigated the interaction of the APOE epsilon2/epsilon3/epsilon4 polymorphism and lipid-lowering therapy in relation to the course of coronary heart disease; the results are contradictory and so far inconclusive. This review summarizes the pharmacogenetic findings related to the influence of APOE gene variation on lipid responses and the prevention of coronary heart disease during lipid-lowering therapy.

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Section: Apoe Polymorphisms and The Response During Lipid-lowering Therapymentioning

confidence: 99%

Pharmacogenetics of Apolipoprotein E Gene During Lipid-Lowering Therapy: Lipid Levels and Prevention of Coronary Heart Disease

et al. 2008

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“…Pharmacophore detection shared by selected input ligand molecules (Ligand75_24, Ligand75_37, Ligand75_49, Ligand75_76, Ezetimibe drug) was checked by PharmaGist (http://bioinfo3d.cs.tau.ac.il/PharmaGist/) which is a ligand-based method (Schneidman-Duhovny et al, 2008). Ezetimibe, a drug used in the treatment of CAD, shown to have significant improvement in lipid and lipoprotein profile (TC, LDL-C, triglycerides and HDL-C) in patients with APOE3 and APOE4 genotypes (Mark et al, 2007). Pharmacophore mapping of the selected ligands showed shared pharmacophore features between the 4 ligands and the Ezetimibe drug, containing 2 hydrophobic contacts and 2 hydrogen bond donors as shown in Figure 5.…”

Section: Resultsmentioning

confidence: 99%

Identification of APOE4 modulators, targeted therapeutic candidates in Coronary Artery Disease, using Molecular Docking studies

Hazarika

Sen

Zawar³

et al. 2021

Preprint

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A significant genetic suspect for coronary artery disease is the pathological adaptation of apolipoprotein E4 (APOE4) through intramolecular interaction. With the prevailing evidence on APOE4 genotype and its prevalence in coronary artery disease, the present study has investigated the protein-ligand binding affinity and unveil the receptor binding abilities of different classes of ligands for APOE4 through molecular docking studies. Structural basis of APOE4 involvement in CAD suggests that the intramolecular domain interactions to be a suitable target for therapeutic intervention. Various classes of ligands including known drugs used in the treatment of CAD, fragment-based stabilizers and their similar structures and molecules with known bioactivity against APOE4 were screened for their binding affinity and further investigated for their interactions with APOE4. Computational studies show the benzyl amide derived structures to be useful candidates in modulation of APOE4. The dynamics of the binding analysis can be further achieved with an in-depth understanding of drug-receptor interactions performing molecular dynamic simulation studies.

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“…Pharmacophore detection shared by selected input ligand molecules (Ligand75_24, Ligand75_37, Ligand75_49, Ligand75_76, Ezetimibe drug) was checked by PharmaGist (http://bioinfo3d.cs.tau.ac.il/PharmaGist/) which is a ligandbased method [38]. Ezetimibe, a drug used in the treatment of CAD, shown to have significant improvement in lipid and lipoprotein profile (TC, LDL-C, triglycerides and HDL-C) in patients with APOE3 and APOE4 genotypes [39]. Pharmacophore mapping of the selected ligands showed shared pharmacophore features between the 4 ligands and the Ezetimibe drug, containing 2 hydrophobic contacts and 2 hydrogen bond donors as shown in Figure 5.…”

Section: Figure 4 (A): Receptor-ligand Interactions Visualized Using Discovery Studio Showing the Amino Acid Residues Interacting Throughmentioning

confidence: 99%

Identification of APOE4 Modulators, Targeted Therapeutic Candidates in Coronary Artery Disease, Using Molecular Docking Studies

Hazarika¹,

Sen²,

Zawar³

et al. 2021

JDDMC

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Investigate the protein-ligand binding affinity and evaluate the receptor binding abilities of different classes of ligands for APOE4 through molecular docking studies. The polymorphic nature of human Apo E gene encodes one of 3 common epsilon (ε) alleles (ε2, ε3, and ε4), reported to influence the risk of cardiovascular diseases. Structural basis of APOE4 involvement in CAD suggests that the intramolecular domain interactions to be a suitable target for therapeutic intervention. Identification of APOE4 modulators, targeted towards therapeutic candidates in CAD using Molecular Docking studies. Various classes of ligands including known drugs used in the treatment of CAD, fragment-based stabilizers and their similar structures and molecules with known bioactivity against APOE4 were screened for their binding affinity and further investigated for their interactions with APOE4. Computational studies show the benzyl amide derived structures to be useful candidates in modulation of APOE4. The protein-ligand binding affinities predicted in the study indicated receptor binding abilities of APOE4 that can lead to have interesting insights on structural conformity of APOE4 and its correlated functional aspects. Understanding modulation of APOE4 can pave ways to use it as biomarker for CAD as well as for its therapeutics. Further analysis of the variation of the docked protein structure, molecular dynamic simulation can be performed to generate a dynamic structure for binding analysis.

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Effects of ezetimibe on lipids and lipoproteins in patients with hypercholesterolemia and different apolipoprotein E genotypes

Cited by 7 publications

References 53 publications

Pharmacogenetics of Apolipoprotein E Gene During Lipid-Lowering Therapy: Lipid Levels and Prevention of Coronary Heart Disease

Pharmacogenetics of Apolipoprotein E Gene During Lipid-Lowering Therapy: Lipid Levels and Prevention of Coronary Heart Disease

Identification of APOE4 modulators, targeted therapeutic candidates in Coronary Artery Disease, using Molecular Docking studies

Identification of APOE4 Modulators, Targeted Therapeutic Candidates in Coronary Artery Disease, Using Molecular Docking Studies

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Effects of ezetimibe on lipids and lipoproteins in patients with hyper­cholesterolemia and different apolipoprotein E genotypes

Cited by 7 publications

References 53 publications

Pharmacogenetics of Apolipoprotein E Gene During Lipid-Lowering Therapy: Lipid Levels and Prevention of Coronary Heart Disease

Pharmacogenetics of Apolipoprotein E Gene During Lipid-Lowering Therapy: Lipid Levels and Prevention of Coronary Heart Disease

Identification of APOE4 modulators, targeted therapeutic candidates in Coronary Artery Disease, using Molecular Docking studies

Identification of APOE4 Modulators, Targeted Therapeutic Candidates in Coronary Artery Disease, Using Molecular Docking Studies

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Effects of ezetimibe on lipids and lipoproteins in patients with hypercholesterolemia and different apolipoprotein E genotypes