De Novo Discovery of Serotonin N-Acetyltransferase Inhibitors

详细信息    查看全文

• 作者：Lawrence M. Szewczuk ; S. Adrian Saldanha ; Surajit Ganguly ; Erin M. Bowers ; Margarita Javoroncov ; Balasubramanyam Karanam ; Jeffrey C. Culhane ; Marc A. Holbert ; David C. Klein ; Ruben Abagyan ; Philip A. C
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 1, 2007
• 年：2007
• 卷：50
• 期：22
• 页码：5330 - 5338
• 全文大小：554K
• 年卷期：v.50,no.22(November 1, 2007)
• ISSN：1520-4804

文摘

Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) is a member of the GCN5N-acetyltransferase (GNAT) superfamily and catalyzes the penultimate step in the biosynthesis of melatonin;a large daily rhythm in AANAT activity drives the daily rhythm in circulating melatonin. We have used astructure-based computational approach to identify the first druglike and selective inhibitors of AANAT.Approximately 1.2 million compounds were virtually screened by 3D high-throughput docking into theactive site of X-ray structures for AANAT, and in total 241 compounds were tested as inhibitors. Onecompound class, containing a rhodanine scaffold, exhibited low micromolar competitive inhibition againstacetyl-CoA (AcCoA) and proved to be effective in blocking melatonin production in pineal cells. Compoundsfrom this class are predicted to bind as bisubstrate inhibitors through interactions with the AcCoA andserotonin binding sites. Overall, this study demonstrates the feasibility of using virtual screening to identifysmall molecules that are selective inhibitors of AANAT.