Discovery of a Novel 5-HT2A Inhibitor by Pharmacophore-based Virtual Screening

高等学校化学研究 ›› 2011, Vol. 27 ›› Issue (4): 655-660.

Discovery of a Novel 5-HT_2A Inhibitor by Pharmacophore-based Virtual Screening

XIONG Zi-jun¹, DU Peng¹, LI Bian¹, XU Li-li¹, ZHEN Xue-chu^2,3* and FU Wei^1*

1. Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, P. R. China;
2. State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China;
3. Department of Pharmacology, College of Pharmacy, Soochow University, Suzhou 215123, P. R. China

收稿日期:2011-05-11 修回日期:2011-06-13 出版日期:2011-07-25 发布日期:2011-06-29
通讯作者: ZHEN Xue-chu;FU Wei E-mail:weifuuh@gmail.com; xczhen@mail.shcnc.ac.cn
基金资助:
Supported by the National High Technology Research and Development Program of China(No.2009AA02Z308), the Major State Basic Research Development Program of China(No.2010CB912601) and the National Natural Science Foundation of China (No.20702009).

Discovery of a Novel 5-HT_2A Inhibitor by Pharmacophore-based Virtual Screening

XIONG Zi-jun¹, DU Peng¹, LI Bian¹, XU Li-li¹, ZHEN Xue-chu^2,3* and FU Wei^1*

1. Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, P. R. China;
2. State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China;
3. Department of Pharmacology, College of Pharmacy, Soochow University, Suzhou 215123, P. R. China

Received:2011-05-11 Revised:2011-06-13 Online:2011-07-25 Published:2011-06-29
Contact: ZHEN Xue-chu;FU Wei E-mail:weifuuh@gmail.com; xczhen@mail.shcnc.ac.cn
Supported by:
Supported by the National High Technology Research and Development Program of China(No.2009AA02Z308), the Major State Basic Research Development Program of China(No.2010CB912601) and the National Natural Science Foundation of China (No.20702009).

摘要/Abstract

摘要： The serotonin 2A(5-HT2A) receptor has been implicated in several neurological conditions and potent 5-HT2A antagonists have therapeutic effects in the treatment of schizo phrenia and depression. In this study, a potent novel 5-HT2A inhibitor 05245768 with a Ki value of (593.89±34.10) nmol/L was discovered by integrating a set of computational approaches and experiments(protein structure prediction, pharmacophore-based virtual screening, automated molecular docking and pharmacological bioassay). The 5-HT2A receptor showed a negatively charged bin- ding pocket. The binding mode of compound 05245768 with 5-HT2A was obtained by GOLD docking procedure, which revealed the conserved interaction between protonated nitrogen in compound 05245768 and carboxylate group of D3.32 at the active site of 5-HT2A.

关键词: Pharmacophore model, Serotonin 2A receptor, Database search, Virtual screening, Molecular docking

Abstract: The serotonin 2A(5-HT2A) receptor has been implicated in several neurological conditions and potent 5-HT2A antagonists have therapeutic effects in the treatment of schizo phrenia and depression. In this study, a potent novel 5-HT2A inhibitor 05245768 with a Ki value of (593.89±34.10) nmol/L was discovered by integrating a set of computational approaches and experiments(protein structure prediction, pharmacophore-based virtual screening, automated molecular docking and pharmacological bioassay). The 5-HT2A receptor showed a negatively charged bin- ding pocket. The binding mode of compound 05245768 with 5-HT2A was obtained by GOLD docking procedure, which revealed the conserved interaction between protonated nitrogen in compound 05245768 and carboxylate group of D3.32 at the active site of 5-HT2A.

Key words: Pharmacophore model, Serotonin 2A receptor, Database search, Virtual screening, Molecular docking

XIONG Zi-jun, DU Peng, LI Bian, XU Li-li, ZHEN Xue-chu* and FU Wei*. Discovery of a Novel 5-HT_2A Inhibitor by Pharmacophore-based Virtual Screening[J]. 高等学校化学研究, 2011, 27(4): 655-660.

XIONG Zi-jun, DU Peng, LI Bian, XU Li-li, ZHEN Xue-chu* and FU Wei*. Discovery of a Novel 5-HT_2A Inhibitor by Pharmacophore-based Virtual Screening[J]. Chemical Research in Chinese Universities, 2011, 27(4): 655-660.

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Discovery of a Novel 5-HT_2A Inhibitor by Pharmacophore-based Virtual Screening

Discovery of a Novel 5-HT_2A Inhibitor by Pharmacophore-based Virtual Screening

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