Identification of Novel Serotonin Transporter Compounds by Virtual Screening

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• 作者：Mari Gabrielsen ; Rafa艂 Kurczab ; Agata Siwek ; Ma艂gorzata Wolak ; Aina W. Ravna ; Kurt Kristiansen ; Irina Kufareva ; Ruben Abagyan ; Gabriel Nowak ; Zdzis艂aw Chilmonczyk ; Ingebrigt Sylte ; Andrzej J. Bojarski
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2014
• 出版时间：March 24, 2014
• 年：2014
• 卷：54
• 期：3
• 页码：933-943
• 全文大小：569K
• 年卷期：v.54,no.3(March 24, 2014)
• ISSN：1549-960X

文摘

The serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) plays an essential role in the termination of serotonergic neurotransmission by removing 5-HT from the synaptic cleft into the presynaptic neuron. It is also of pharmacological importance being targeted by antidepressants and psychostimulant drugs. Here, five commercial databases containing approximately 3.24 million drug-like compounds have been screened using a combination of two-dimensional (2D) fingerprint-based and three-dimensional (3D) pharmacophore-based screening and flexible docking into multiple conformations of the binding pocket detected in an outward-open SERT homology model. Following virtual screening (VS), selected compounds were evaluated using in vitro screening and full binding assays and an in silico hit-to-lead (H2L) screening was performed to obtain analogues of the identified compounds. Using this multistep VS/H2L approach, 74 active compounds, 46 of which had K_i values of 鈮?000 nM, belonging to 16 structural classes, have been identified, and multiple compounds share no structural resemblance with known SERT binders.