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论文类型：期刊论文

发表时间：2014-08-01

发表刊物：MEDICINAL CHEMISTRY RESEARCH

收录刊物：SCIE、Scopus

卷号：23

期号：8

页面范围：3916-3926

ISSN号：1054-2523

关键字：Retinoic acid receptor alpha; Pharmacophore model; Validation; Virtual screening

摘要：Retinoic acid receptor alpha (RAR alpha) has been considered as one of the most important targets for the treatment of acute promyelocytic leukemia. To discover more novel lead compounds, ligand-based pharmacophore modeling of a series of structurally diverse RAR alpha agonists was applied to acquire the binding model (KI pharmacophore model) and the efficacy model (EC50 pharmacophore model) of RAR alpha. In this paper, a three-dimensional quantitative structure-activity relationship (3D-QSAR) in Discovery Studio 2.5 was used to generate pharmacophore models. Via Fischer's randomization validation and maximum unbiased validation, the best pharmacophore model for KI pharmacophore model was Hypo1K and for EC50 pharmacophore model was Hypo7E. Virtual screening of National Cancer Institute database using Hypo1K and Hypo7E was performed, respectively. Six potent compounds in the retrieved hits with a CAS number were confirmed to be effective on leukemia cell lines and other tumors in the literatures. As evident from the validation and the biological screening results, it can be concluded that the Hypo1K and Hypo7E were reliable and useful tools for lead optimization of novel RAR alpha agonists.