In silico drug discovery of flavonoids as potential PPAR agonists in treatment of metabolic syndrome

Q4 Pharmacology, Toxicology and Pharmaceutics

Pharmaceutical Sciences Asia Pub Date : 2023-01-01 DOI:10.29090/psa.2023.02.22.334

B. Nguyen, Phuong Chau Uyen Nguyen, K. Nguyen, Phat Nguyen Pham, P. Nguyen

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Abstract

Peroxisome proliferative activating receptors (PPARs) are a subfamily of three ligand-inducible transcription factors which are important targets in drug discovery for the treatment of metabolic syndrome (MetS). This study aimed to discover flavonoids as potential PPAR agonists. The results showed that the generated 3D-pharmacophore model for PPAR activators included four pharmacophoric features, namely one hydrophobic, two hydrogen acceptors and one hydrogen donor points, respectively. This pharmacophore model had the specificity, accuracy and sensitivity were 74%, 74% and 75%, respectively. 648 out of 3,848 flavonoid compounds satisfied all the features of the chosen pharmacophore model. Molecular docking results demonstrated that these compounds bound well in the binding site of PPARs. Among them, F85 was the most potential compound with the binding affinities of PPARα (-9.6 kcal.mol -1 ), PPARγ (-10.5 kcal.mol -1 ), PPARδ (-9.5 kcal.mol -1 ). Through forming hydrogen bonds and hydrophobic interactions with the key residues, F85 could reach deeper into the binding pocket of the receptors. Moreover, F85 was stable in the binding site of PPARs during the molecular dynamics simulations. Therefore, this compound was deemed to be potent as PPAR agonists.

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黄酮类化合物作为潜在的PPAR激动剂治疗代谢综合征的硅片药物发现

过氧化物酶体增殖激活受体(PPARs)是三种配体诱导转录因子的亚家族，是代谢综合征(MetS)治疗药物发现的重要靶点。本研究旨在发现类黄酮作为潜在的PPAR激动剂。结果表明，生成的PPAR活化剂3d药效团模型包含4个药效团特征，分别为1个疏水点、2个氢受体点和1个氢供体点。该药效团模型的特异性为74%，准确性为74%，敏感性为75%。3848个类黄酮化合物中有648个满足所选药效团模型的所有特征。分子对接结果表明，这些化合物在PPARs的结合位点结合良好。其中，F85对PPARα (-9.6 kcal.mol -1)、PPARγ (-10.5 kcal.mol -1)、PPARδ (-9.5 kcal.mol -1)的结合亲和力最强。通过与关键残基形成氢键和疏水相互作用，F85可以深入到受体的结合口袋中。此外，在分子动力学模拟中，F85在PPARs的结合位点是稳定的。因此，该化合物被认为是有效的PPAR激动剂。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pharmaceutical Sciences Asia Pharmacology, Toxicology and Pharmaceutics-Pharmacology, Toxicology and Pharmaceutics (all)

CiteScore

0.90

自引率

0.00%

发文量

期刊介绍： The Pharmaceutical Sciences Asia (PSA) journal is a double-blinded peer-reviewed journal in English published quarterly, by the Faculty of Pharmacy, Mahidol University, Thailand. The PSA journal is formerly known as Mahidol University Journal of Pharmaceutical Sciences and committed to the timely publication of innovative articles and reviews. This journal is available in both printed and electronic formats. The PSA journal aims at establishing a publishing house that is open to all. It aims to disseminate knowledge; provide a learned reference in the field; and establish channels of communication between academic and research expert, policy makers and executives in industry and investment institutions. The journal publishes research articles, review articles, and scientific commentaries on all aspects of the pharmaceutical sciences and multidisciplinary field in health professions and medicine. More specifically, the journal publishes research on all areas of pharmaceutical sciences and related disciplines: Clinical Pharmacy Drug Synthesis and Discovery Targeted-Drug Delivery Pharmaceutics Biopharmaceutical Sciences Phytopharmaceutical Sciences Pharmacology and Toxicology Pharmaceutical Chemistry Nutraceuticals and Functional Foods Natural Products Social, Economic, and Administrative Pharmacy Clinical Drug Evaluation and Drug Policy Making Antimicrobials, Resistance and Infection Control Pharmacokinetics and Pharmacodynamics.