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Structural insights into the origin of phosphoinositide 3-kinase inhibition
Structural Chemistry ( IF 1.7 ) Pub Date : 2020-03-06 , DOI: 10.1007/s11224-020-01510-2
Safoura Hariri , Behnam Rasti , Mirsasan Mirpour , Gholamreza Vaghar-Lahijani , Farnoosh Attar , Fereshteh Shiri

Class I phosphoinositide 3-kinases (PI3Ks) are currently considered as significant targets for the development of novel pharmaceuticals to treat cancers and inflammatory diseases. Since the subfamilies are differently involved in related disorders and within different subcellular compartments, the development of specific subfamily-selective inhibitors seems pertinent. However, discovery of compounds with capability to block a specific isoform of PI3K still remains as a major challenge. Therefore, herein, a combination of proteochemometric (PCM) modeling and molecular docking simulation was applied to investigate the chemical interaction space governed by α and β isoforms of PI3K and their inhibitors. Since achieving selectivity can be facilitated by considering the information of both ligand and receptor, the interaction space and selectivity of different chemical compounds towards different PI3K isoforms were explored via PCM modeling. Several approaches were applied to validate the predictivity and the robustness of the constructed model. Excellent values of 0.95, 0.85, and 0.77 were observed for the goodness of fit ( R 2 ), internal cross-validation ( Q 2 ), and external validation ( Q ext 2 ), respectively. The practical application of this information was revealed via the design of a few novel compounds whereby structural modifications to the compound can exert influences on the selectivity against PI3Kα and PI3Kβ. Applying molecular docking approach, binding energies and molecular interactions were investigated for the novel compounds against both PI3Kα and PI3Kβ. Molecular docking analysis of novel design compounds was highly compatible with the PCM-based predicted biological activities. These results show that our model provided knowledge on the structural features of compounds which is promising for the design of new selective inhibitors.

中文翻译:

对磷酸肌醇 3-激酶抑制起源的结构洞察

I 类磷酸肌醇 3-激酶 (PI3K) 目前被认为是开发治疗癌症和炎症疾病的新型药物的重要靶点。由于亚家族在相关疾病和不同亚细胞区室中的参与程度不同,因此开发特定的亚家族选择性抑制剂似乎是相关的。然而,发现具有阻断特定 PI3K 同工型能力的化合物仍然是一个主要挑战。因此,在本文中,蛋白质化学计量学 (PCM) 建模和分子对接模拟的组合被应用于研究由 PI3K 的 α 和 β 亚型及其抑制剂控制的化学相互作用空间。由于考虑配体和受体的信息可以促进实现选择性,通过 PCM 建模探索了不同化合物对不同 PI3K 异构体的相互作用空间和选择性。应用多种方法来验证所构建模型的预测性和稳健性。分别观察到拟合优度 (R 2 )、内部交叉验证 ( Q 2 ) 和外部验证 ( Q ext 2 ) 的优异值 0.95、0.85 和 0.77。这些信息的实际应用是通过设计一些新化合物来揭示的,其中对化合物的结构修饰可以影响对 PI3Kα 和 PI3Kβ 的选择性。应用分子对接方法,研究了针对 PI3Kα 和 PI3Kβ 的新型化合物的结合能和分子相互作用。新设计化合物的分子对接分析与基于 PCM 的预测生物活性高度兼容。这些结果表明,我们的模型提供了关于化合物结构特征的知识,这对于设计新的选择性抑制剂是有希望的。
更新日期:2020-03-06
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