Multi-conformation dynamic pharmacophore modeling of the peroxisome proliferator-activated receptor 纬 for the discovery of novel agonists

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• 作者：Young-sik Sohn ; Chanin Park ; Yuno Lee ; Songmi Kim ; Sundarap ; ian Thangap ; ian ; Yongseong Kim ; Hyong-Ha Kim ; Jung-Keun Suh ; Keun Woo Lee
• 关键词：Peroxisome proliferator-activated receptor 纬 ; Multi-conformation dynamic pharmacophore modeling ; Molecular dynamics simulation ; Drug design ; Type 2 diabetes
• 刊名：Journal of Molecular Graphics and Modelling
• 出版年：November, 2013
• 年：2013
• 卷：46
• 期：Complete
• 页码：1-9
• 全文大小：3631 K

文摘

Activation of the peroxisome proliferator-activated receptor 纬 (PPAR纬) is important for the treatment of type 2 diabetes and obesity through the regulation of glucose metabolism and fatty acid accumulation. Hence, the discovery of novel PPAR纬 agonists is necessary to overcome these diseases. In this study, a newly developed approach, multi-conformation dynamic pharmacophore modeling (MCDPM), was used for screening candidate compounds that can properly bind PPAR纬. Highly populated structures obtained from molecular dynamics (MD) simulations were selected by clustering analysis. Based on these structures, pharmacophore models were generated from the ligand-binding pocket and then validated to check the rationality. Consequently, two hits were retrieved as final candidates by utilizing virtual screening and molecular docking simulations. These compounds can be used in the design of novel PPAR纬 agonists.