用于设计亚型选择性过氧化物酶体增殖物激活受体-α（PPAR-α）激动剂的生物学评价及结构见解
Biological evaluation and structural insights for design of subtype-selective peroxisome proliferator activated receptor-α (PPAR-α) agonists.
作者信息
Gangwal Rahul P, Damre Mangesh V, Das Nihar R, Sharma Shyam S, Sangamwar Abhay T
机构信息
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sect-67, S.A.S. Nagar, Punjab 160 062, India.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sect-67, S.A.S. Nagar, Punjab 160 062, India.
出版信息
Bioorg Med Chem Lett. 2015 Jan 15;25(2):270-5. doi: 10.1016/j.bmcl.2014.11.052. Epub 2014 Nov 26.
Peroxisome proliferator activated receptors-α (PPAR-α) control the expression of several genes involved in diseases like diabetes, hyperlipidaemia, and inflammatory disorders. Herein, we report the biological evaluation of recently identified hits from pharmacophore based virtual screening. The most potent hits, ZINC17167211, ZINC06472206 and ZINC08438472 showed EC50 values of 0.16, 1.1 and 12.1nM in PPAR-α agonist assay, respectively. Further, comparative docking and molecular dynamics analysis of selective PPAR-α agonists revealed that Thr279, Ala333, Lys358 and Met325 residues play an important role in the selective PPAR-α agonistic activity. The insights from docking and molecular dynamic studies will serve as a guideline for the development of potent and selective PPAR-α agonists.
过氧化物酶体增殖物激活受体-α（PPAR-α）控制着一些与糖尿病、高脂血症和炎症性疾病等相关疾病有关的基因的表达。在此，我们报告了基于药效团虚拟筛选最近鉴定出的活性化合物的生物学评估。最有效的活性化合物ZINC17167211、ZINC06472206和ZINC08438472在PPAR-α激动剂试验中的EC50值分别为0.16、1.1和12.1 nM。此外，对选择性PPAR-α激动剂的比较对接和分子动力学分析表明，Thr279、Ala333、Lys358和Met325残基在选择性PPAR-α激动活性中起重要作用。对接和分子动力学研究的见解将为开发强效和选择性PPAR-α激动剂提供指导。
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