ArticleInternational journal of molecular sciences2020
Elucidation of Molecular Mechanism of a Selective PPARα Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations.
Article in International journal of molecular sciences, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 24 citations in OpenAlex.
- PPARα: Linking Cardiac Metabolism to Therapeutic Opportunities in Cardiovascular Diseases.Cells · 2026Review
- Impact of Chromium Picolinate on Breast Muscle Metabolomics and Glucose and Lipid Metabolism-Related Genes in Broilers Under Heat Stress.Animals : an open access journal from MDPI · 2025Article
- Autophagy and the peroxisome proliferator-activated receptor signaling pathway: A molecular ballet in lipid metabolism and homeostasis.Molecular and cellular biochemistry · 2025Review
- Selective PPARα Modulator (SPPARMα) in the Era of the MASLD Pandemic: Current Insights and Future Prospects.Yonago acta medica · 2025Review
- Emerging Therapies for the Treatment of Atherosclerotic Cardiovascular Disease: From Bench to Bedside.International journal of molecular sciences · 2023Review
- Atractylodin Ameliorates Colitis via PPARα Agonism.International journal of molecular sciences · 2023Article
- Peptide Helix-YPPAR research · 2023Article
- PPARα: An emerging target of metabolic syndrome, neurodegenerative and cardiovascular diseases.Frontiers in endocrinology · 2022Review
- In Silico-Based Design and In Vivo Evaluation of an Anthranilic Acid Derivative as a Multitarget Drug in a Diet-Induced Metabolic Syndrome Model.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Mechanisms Mediating the Regulation of Peroxisomal Fatty Acid Beta-Oxidation by PPARα.International journal of molecular sciences · 2021Review
- Effects of pemafibrate on glucose metabolism markers and liver function tests in patients with hypertriglyceridemia: a pooled analysis of six phase 2 and phase 3 randomized double-blind placebo-controlled clinical trials.Cardiovascular diabetology · 2021Article
- Selective Peroxisome Proliferator-Activated Receptor Alpha Modulators (SPPARMα) in the Metabolic Syndrome: Is Pemafibrate Light at the End of the Tunnel?Current atherosclerosis reports · 2021Review
- Small-Molecule Modulation of PPARs for the Treatment of Prevalent Vascular Retinal Diseases.International journal of molecular sciences · 2020Review
- Article
- PPARα Agonist Oral Therapy in Diabetic Retinopathy.Biomedicines · 2020Review
- Selective Peroxisome Proliferator-Activated Receptor Alpha Modulators (SPPARMα): New Opportunities to Reduce Residual Cardiovascular Risk in Chronic Kidney Disease?Current atherosclerosis reports · 2020Review
- Review
- Structural Basis for PPARα Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives.Scientific reports · 2020Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
The selective PPARα modulator (SPPARMα) is expected to medicate dyslipidemia with minimizing adverse effects. Recently, pemafibrate was screened from the ligand library as an SPPARMα bearing strong potency. Several clinical pieces of evidence have proved the usefulness of pemafibrate as a medication; however, how pemafibrate works as a SPPARMα at the molecular level is not fully known. In this study, we investigate the molecular mechanism behind its novel SPPARMα character through a combination of approaches of X-ray crystallography, isothermal titration calorimetry (ITC), and fragment molecular orbital (FMO) analysis. ITC measurements have indicated that pemafibrate binds more strongly to PPARα than to PPARγ. The crystal structure of PPARα-ligand binding domain (LBD)/pemafibrate/steroid receptor coactivator-1 peptide (SRC1) determined at 3.2 Å resolution indicates that pemafibrate binds to the ligand binding pocket (LBP) of PPARα in a Y-shaped form. The structure also reveals that the conformation of the phenoxyalkyl group in pemafibrate is flexible in the absence of SRC1 coactivator peptide bound to PPARα; this gives a freedom for the phenoxyalkyl group to adopt structural changes induced by the binding of coactivators. FMO calculations have indicated that the accumulation of hydrophobic interactions provided by the residues at the LBP improve the interaction between pemafibrate and PPARα compared with the interaction between fenofibrate and PPARα.
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