通过基于晶体结构的药效团模型构建和定量构效关系分析的虚拟筛选发现新型磷酸肌醇 3-激酶 δ（PI3Kδ）抑制剂。
Discovery of New Phosphoinositide 3-kinase Delta (PI3Kδ) Inhibitors via Virtual Screening using Crystallography-derived Pharmacophore Modelling and QSAR Analysis.
机构信息
Faculty of Pharmacy, Zarqa University, P.O. Box 132222, Zarqa, 13132, Jordan.
Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman, Jordan.
出版信息
Med Chem. 2019;15(6):588-601. doi: 10.2174/1573406415666190222125333.
BACKGROUND
PI3Kδ is predominantly expressed in hematopoietic cells and participates in the activation of leukocytes. PI3Kδ inhibition is a promising approach for treating inflammatory diseases and leukocyte malignancies. Accordingly, we decided to model PI3Kδ binding.
METHODS
Seventeen PI3Kδ crystallographic complexes were used to extract 94 pharmacophore models. QSAR modelling was subsequently used to select the superior pharmacophore(s) that best explain bioactivity variation within a list of 79 diverse inhibitors (i.e., upon combination with other physicochemical descriptors).
RESULTS
The best QSAR model (r2 = 0.71, r2 LOO = 0.70, r2 press against external testing list of 15 compounds = 0.80) included a single crystallographic pharmacophore of optimal explanatory qualities. The resulting pharmacophore and QSAR model were used to screen the National Cancer Institute (NCI) database for new PI3Kδ inhibitors. Two hits showed low micromolar IC50 values.
CONCLUSION
Crystallography-based pharmacophores were successfully combined with QSAR analysis for the identification of novel PI3Kδ inhibitors.
背景
PI3Kδ 主要在造血细胞中表达，并参与白细胞的激活。PI3Kδ 抑制是治疗炎症性疾病和白细胞恶性肿瘤的一种有前途的方法。因此，我们决定对 PI3Kδ 结合进行建模。
方法
使用十七个 PI3Kδ 晶体复合物来提取 94 个药效团模型。随后使用 QSAR 建模来选择最佳药效团，以最佳解释一系列 79 种不同抑制剂（即与其他物理化学描述符结合使用时）的生物活性变化。
结果
最佳 QSAR 模型（r2 = 0.71、r2 LOO = 0.70、r2 press against external testing list of 15 compounds = 0.80）包含单一具有最佳解释质量的晶体药效团。由此产生的药效团和 QSAR 模型被用于筛选国家癌症研究所（NCI）数据库中的新型 PI3Kδ 抑制剂。两种化合物显示出低微摩尔 IC50 值。
结论
基于晶体的药效团成功地与 QSAR 分析相结合，用于鉴定新型 PI3Kδ 抑制剂。
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