Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
Comb Chem High Throughput Screen. 2022;25(9):1450-1461. doi: 10.2174/1386207324666210628114216.
The Peroxisome Proliferator-Activated Receptors (PPARs) are ligandactivated transcription factors belonging to the nuclear receptor family. The roles of PPARα in fatty acid oxidation and PPARγ in adipocyte differentiation and lipid storage have been widely characterized. Compounds with dual PPARα/γ activity have been proposed, combining the benefits of insulin sensitization and lipid lowering into one drug, allowing a single drug to reduce hyperglycemia and hyperlipidemia while preventing the development of cardiovascular complications.
The new PPARα/γ agonists were screened through virtual screening of pharmacophores and molecular dynamics simulations. First, in the article, the constructed pharmacophore was used to screen the Ligand Expo Components-pub database to obtain the common structural characteristics of representative PPARα/γ agonist ligands. Then, the accepted ligand structure was modified and replaced to obtain 12 new compounds. Using molecular docking, ADMET and molecular dynamics simulation methods to screen the designed 12 ligands, analyze their docking scores when they bind to the PPARα/γ dual targets, their stability and pharmacological properties when they bind to the PPARα/γ dual targets.
We performed pharmacophore-based virtual screening for 22949 molecules in Ligand Expo Components-pub database. The compounds that were superior to the original ligand were performed structural analysis and modification, and a series of compounds with novel structures were designed. Using precise docking, ADMET prediction and molecular dynamics methods to screen and verify newly designed compounds, and the above compounds show higher docking scores and lower side effects.
9 new PPARα/γ agonists were obtained by pharmacophore modeling, docking analysis and molecular dynamics simulation.
过氧化物酶体增殖物激活受体 (PPAR) 是配体激活的转录因子，属于核受体家族。PPARα 在脂肪酸氧化中的作用和 PPARγ 在脂肪细胞分化和脂质储存中的作用已得到广泛研究。已经提出了具有双重 PPARα/γ 活性的化合物，将胰岛素增敏和降血脂的益处结合在一种药物中，使一种药物能够降低高血糖和高血脂，同时预防心血管并发症的发展。
通过药效团虚拟筛选和分子动力学模拟对新型 PPARα/γ 激动剂进行筛选。首先，在本文中，使用构建的药效团筛选 Ligand Expo Components-pub 数据库，以获得代表性 PPARα/γ 激动剂配体的共同结构特征。然后，对已接受的配体结构进行修饰和替换，得到 12 种新化合物。采用分子对接、ADMET 和分子动力学模拟方法对设计的 12 种配体进行筛选，分析它们与 PPARα/γ 双靶结合的对接评分、与 PPARα/γ 双靶结合的稳定性和药理学性质。
我们对 Ligand Expo Components-pub 数据库中的 22949 个分子进行了基于药效团的虚拟筛选。对优于原始配体的化合物进行结构分析和修饰，设计了一系列具有新颖结构的化合物。采用精确对接、ADMET 预测和分子动力学方法对新设计的化合物进行筛选和验证，上述化合物表现出更高的对接评分和更低的副作用。
通过药效团建模、对接分析和分子动力学模拟，获得了 9 种新型 PPARα/γ 激动剂。
