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Chemical function-based pharmacophore generation of selective κ-opioid receptor agonists by catalyst and phase

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Abstract

Two chemical function-based pharmacophore models of selective κ-opioid receptor agonists were generated by using two different programs: Catalyst/HypoGen and Phase. The best output hypothesis (Hypo1) of HypoGen consisted of five features: one hydrogen-bond acceptor (HA), three hydrophobic points (HY), and one positive ionizable function (PI). The highest scoring model (Hypo2) produced by Phase comprised four features: one acceptor (A), one positive ionizable function (P), and two aromatic ring features (R). These two models (Hypo1 and Hypo2) were then validated by test set prediction and enrichment factors. They were shown to be able to identify highly potent κ-agonists within a certain range, and satisfactory enrichments were achieved. The features of these two pharmacophore models were similar and consistent with experiment data. The models produced here were also generally in accord with other reported models. Therefore, our pharmacophore models were considered as valuable tools for 3D virtual screening, and could be useful for designing novel κ-agonists.

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Acknowledgments

The authors greatly appreciate the software support for Catalyst from Prof. Hualiang Jiang of the Shanghai Institute of Materia Medica, CAS. This work was supported by National Natural Science Foundation of China (Grant 30600785), Shanghai Rising-Star Program (Grant 07QA14016), and Key 863 High-Tech Program (Grant 2006AA020404).

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  1. Laboratory of Molecular Modeling and Design, School of Pharmacy, East China University of Science and Technology, Box 268, 130 Meilong Road, Shanghai, 200237, China

    Jing Zhang, Guixia Liu & Yun Tang

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  1. Jing Zhang
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  2. Guixia Liu
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Correspondence to Guixia Liu.

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Zhang, J., Liu, G. & Tang, Y. Chemical function-based pharmacophore generation of selective κ-opioid receptor agonists by catalyst and phase. J Mol Model 15, 1027–1041 (2009). https://doi.org/10.1007/s00894-008-0418-5

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