Receptor- and Ligand-Based Study on Novel 2,2′-Bithienyl Derivatives as Non-Peptidic AANAT Inhibitors

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• 作者：Alban Lepailleur ; Stphane Lematre ; Xiao Feng ; Jana Sopkova-de Oliveira Santos ; Philippe Delagrange ; Jean Boutin ; Pierre Renard ; Ronan Bureau ; Sylvain Rault
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2010
• 出版时间：March 22, 2010
• 年：2010
• 卷：50
• 期：3
• 页码：446-460
• 全文大小：633K
• 年卷期：v.50,no.3(March 22, 2010)
• ISSN：1549-960X

文摘

Arylalkylamine N-acetyl transferase (serotonin N-acetyl transferase, AANAT) is a critical enzyme in the light-mediated regulation of melatonin production and circadian rythm. With the objective of discovering new chemical entities with inhibitory potencies against AANAT, a medium-throughput screening campaign was performed on a chemolibrary. We found a class of molecules based on a 2,2′-bithienyl scaffold, and compound 1 emerged as a first hit. Herein, we describe our progress from hit discovery and to optimization of this new class of compounds. To complete the study, computational approaches were carried out: a docking study which provided insights into the plausible binding modes of these new AANAT inhibitors and a three-dimensional quantitative structure−activity relationship study that applied comparative molecular field analysis (CoMFA) methodology. Several CoMFA models were developed (variable alignments and options), and the best predictive one yields good statistical results (q² = 0.744, r² = 0.891, and s = 0.273). The resulting CoMFA contour maps were used to illustrate the pharmacomodulations relevant to the biological activities in this series of analogs and to design new active inhibitors. This novel series of 2,2′-bithienyl derivatives gives new insights into the design of AANAT inhibitors.