环氧化酶-2抑制剂帕瑞昔布通过[具体方法1]和[具体方法2]检测被揭示为过氧化物酶体增殖物激活受体γ（PPAR-γ）激动剂。

Cyclooxygenase-2 Inhibitor Parecoxib Was Disclosed as a PPAR-γ Agonist by and Assay.

作者信息

Xiao Bin, Li Dan-Dan, Wang Ying, Kim Eun La, Zhao Na, Jin Shang-Wu, Bai Dong-Hao, Sun Li-Dong, Jung Jee H

机构信息

Laboratory of Clinical Pharmacy, Ordos Central Hospital, Ordos School of Clinical Medicine, Inner Mongolia Medical University, Ordos 017000, China.

College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.

出版信息

Biomol Ther (Seoul). 2021 Sep 1;29(5):519-526. doi: 10.4062/biomolther.2021.008.

DOI:10.4062/biomolther.2021.008

PMID:33883322

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8411028/

Abstract

In a search for effective PPAR-γ agonists, 110 clinical drugs were screened via molecular docking, and 9 drugs, including parecoxib, were selected for subsequent biological evaluation. Molecular docking of parecoxib to the ligand-binding domain of PPAR-γ showed high binding affinity and relevant binding conformation compared with the PPAR-γ ligand/antidiabetic drug rosiglitazone. Per the docking result, parecoxib showed the best PPAR-γ transactivation in Ac2F rat liver cells. Further docking simulation and a luciferase assay suggested parecoxib would be a selective (and partial) PPAR-γ agonist. PPAR-γ activation by parecoxib induced adipocyte differentiation in 3T3-L1 murine preadipocytes. Parecoxib promoted adipogenesis in a dose-dependent manner and enhanced the expression of adipogenesis transcription factors PPAR-γ, C/EBPα, and C/EBPβ. These data indicated that parecoxib might be utilized as a partial PPAR-γ agonist for drug repositioning study.

摘要

在寻找有效的过氧化物酶体增殖物激活受体γ（PPAR-γ）激动剂的过程中，通过分子对接筛选了110种临床药物，包括帕罗西汀在内的9种药物被选出来进行后续的生物学评估。与PPAR-γ配体/抗糖尿病药物罗格列酮相比，帕罗西汀与PPAR-γ配体结合域的分子对接显示出高结合亲和力和相关结合构象。根据对接结果，帕罗西汀在Ac2F大鼠肝细胞中表现出最佳的PPAR-γ反式激活作用。进一步的对接模拟和荧光素酶测定表明，帕罗西汀可能是一种选择性（部分）PPAR-γ激动剂。帕罗西汀激活PPAR-γ可诱导3T3-L1小鼠前脂肪细胞的脂肪细胞分化。帕罗西汀以剂量依赖的方式促进脂肪生成，并增强脂肪生成转录因子PPAR-γ、C/EBPα和C/EBPβ的表达。这些数据表明，帕罗西汀可作为部分PPAR-γ激动剂用于药物重新定位研究。