Pharmacophore Model for Wnt/Porcupine Inhibitors and Its Use in Drug Design

详细信息    查看全文

• 作者：Anders Poulsen ; Soo Yei Ho ; Weiling Wang ; Jenefer Alam ; Duraiswamy A. Jeyaraj ; Shi Hua Ang ; Eldwin Sum Wai Tan ; Grace Ruiting Lin ; Vivien Wei Wen Cheong ; Zhiyuan Ke ; May Ann Lee ; Thomas H. Keller
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2015
• 出版时间：July 27, 2015
• 年：2015
• 卷：55
• 期：7
• 页码：1435-1448
• 全文大小：726K
• ISSN：1549-960X

文摘

Porcupine is a component of the Wnt pathway which regulates cell proliferation, migration, stem cell self-renewal, and differentiation. The Wnt pathway has been shown to be dysregulated in a variety of cancers. Porcupine is a membrane bound O-acyltransferase that palmitoylates Wnt. Inhibiting porcupine blocks the secretion of Wnt and effectively inhibits the Wnt pathway. Using high throughput screening, we have identified a number of novel porcupine inhibitors with diverse scaffolds. The pharmacophore requirements for our porcupine inhibitors were elucidated, and a pharmacophore model is proposed. Our compounds as well as all currently published porcupine inhibitors may be fitted to this model in low energy conformations with good superimposition of the pharmacophore elements. The model also explains the stereochemical requirements of our chiral porcupine inhibitors. The pharmacophore model was successfully used for designing 3 new series of porcupine inhibitors having a tricyclic xantine, a phtalimide, or a piperidine鈥搈aleimide scaffold.