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Molecular modeling studies of quinazolinone derivatives as novel PI3Kδ selective inhibitors

机译：喹唑啉酮衍生物作为新型PI3Kδ选择性抑制剂的分子模型研究

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The forced expression of phosphoinositide 3-kinase δ (PI3Kδ) in B cells was found to be oncogenic, rendering PI3Kδ an attractive drug target for chronic lymphocytic leukaemia. This study aimed to systemically explore the interaction mechanism of novel quinazolinone scaffold-based derivatives as PI3Kδ inhibitors using 3D-QSAR, molecular docking, pharmacophore model and molecular dynamics (MD) simulations. The 3D-QSAR models CoMFA, CoMSIA and Topomer CoMFA were established to discover critical structural factors affecting PI3Kδ inhibitory activity. The models showed suitable reliabilities (q2 0.741, 0.712 and 0.711) and predictive abilities (rpred2 0.851, 0.738 and 0.828, respectively). Contour maps indicated that the bioactivity of PI3Kδ inhibitor was affected most by electrostatic and hydrophobic fields. The Surflex-Dock and pharmacophore model result showed that enhancing the H-bond interaction of the key substituents around the 2- and 4-positions of pyrimidine with Glu826, Val828 and Asp911, as well as the electrostatic interactions of substituents around the 3-position of benzene with Ser831, Asp832 and Asn836, significantly affected the improvement in the activity and stability of the inhibitor. Based on these results, 10 novel PI3Kδ inhibitors with higher predicted activity and binding affinity were designed by introducing the heterocycles pyrrolopyridine or purine. 10 ns MD simulations further study the stable docking conformation of designed compounds, which showed strong hydrogen bond interactions with key residues Ser831 and Asp832 in a propeller-like fashion. These results provided strong guidance for the discovery and optimization of novel potent PI3Kδ selective inhibitors.
机译：发现磷酸肌醇3-激酶δ（PI3Kδ）在B细胞中的强制表达是致癌的，使PI3Kδ成为慢性淋巴细胞性白血病的诱人药物靶标。本研究旨在通过3D-QSAR，分子对接，药效团模型和分子动力学（MD）模拟，系统地探索基于喹唑啉酮支架的新型衍生物作为PI3Kδ抑制剂的相互作用机理。建立3D-QSAR模型CoMFA，CoMSIA和Topomer CoMFA以发现影响PI3Kδ抑制活性的关键结构因素。模型显示出适当的可靠性（ q 2 0.741、0.712和0.711）和预测能力（ r pred 2 分别为0.851、0.738和0.828）。等高线图表明，PI3Kδ抑制剂的生物活性受静电场和疏水场影响最大。 Surflex-Dock和药效团模型结果表明，增强了嘧啶在2和4位附近的关键取代基与Glu826，Val828和Asp911的H键相互作用，以及在3位附近的取代基的静电相互作用苯与Ser831，Asp832和Asn836的混合物显着影响抑制剂的活性和稳定性。基于这些结果，通过引入杂环吡咯并吡啶或嘌呤设计了10种具有较高预测活性和结合亲和力的新型PI3Kδ抑制剂。 10 ns的MD模拟进一步研究了所设计化合物的稳定对接构象，该构象显示出与关键残基Ser831和Asp832呈螺旋桨状的强烈氢键相互作用。这些结果为新型有效PI3Kδ选择性抑制剂的发现和优化提供了有力指导。

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