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Insights into binding modes of 5-HT2c receptor antagonists with ligand-based and receptor-based methods

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Abstract

5-hydroxytryptamine-2c (5-HT2c) receptor antagonists have clinical utility in the management of nervous system. In this work, ligand-based and receptor-based methods were used to investigate the binding mode of h5-HT2c receptor antagonists. First, the pharmacophore modeling of the h5-HT2c receptor antagonists was carried out by CATALYST. Then, the h5-HT2c antagonists were docked to the h5-HT2c receptor model. Subsequently, the comprehensive analysis of the pharmacophore and docking results revealed the structure-activity relationship of 5-HT2c receptor antagonists and the key residues involved in the interactions. For example, three hydrophobic points in the ligands corresponded to the region surrounded by Val135, Val208, Phe214, Ala222, Phe327, Phe328 and Val354 of the h5-HT2c receptor. The carbonyl group of compound 1 formed a hydrogen bond with Asn331. The nitrogen atom in the piperidine of compound 1 corresponding to the positive ionizable position of the best pharmacophore formed the electrostatic interactions with the carbonyl of Asp134, Asn331 and Val354, and with the hydroxyl group of Ser334. In addition, a predictive CoMFA model was developed based on the 24 compounds that were used as the training set in the pharmacophore modeling. Our results were not only useful to explore the detailed mechanism of the interactions between the h5-HT2c receptor and antagonists, but also provided suggestions in the discovery of novel 5-HT2c receptor antagonists.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant 30973642), the Fundamental Research Funds for the Central Universities (Grant 0914035), the Program for New Century Excellent Talents in University (Grant NCET-08-0774), the 863 High-Tech Project (Grant 2006AA020404) and the 111 Project of China (Grant B07023).

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Authors and Affiliations

  1. School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China

    Chunhua Lu, Fangfang Jin, Cui Li, Weihua Li, Guixia Liu & Yun Tang

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  1. Chunhua Lu
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  2. Fangfang Jin
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  3. Cui Li
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  4. Weihua Li
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  5. Guixia Liu
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Correspondence to Guixia Liu or Yun Tang.

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Fig. S1

Ramachandran plot of the constructed h5-HT2cR model (DOC 50 kb)

Fig. S2

The diagram of the WHAT-IF quality scores for the modeled 5-HT2cR (DOC 500 kb)

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Lu, C., Jin, F., Li, C. et al. Insights into binding modes of 5-HT2c receptor antagonists with ligand-based and receptor-based methods. J Mol Model 17, 2513–2523 (2011). https://doi.org/10.1007/s00894-010-0936-9

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  • DOI: https://doi.org/10.1007/s00894-010-0936-9

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