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主管单位 工业和信息化部 主办单位 哈尔滨工业大学 主编 任南琪 国际刊号ISSN 1672-5565 国内刊号CN 23-1513/Q

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引用本文:王昭志,贺宏吉,仲春红,卡迪热娅·艾克拉木,白静雅,王梅.设计与筛选靶向PI3Kα的去氢骆驼蓬碱衍生物及其分子动力学验证[J].生物信息学,2024,22(3):204-216.
WANG Zhaozhi,HE Hongji,ZHONG Chunhong,KADIREYA Aikelamu,BAI Jingya,WANG Mei.Design and screening of dehydrogenated harmine derivatives targeting PI3Kα and their molecular dynamics validation[J].Chinese Journal of Bioinformatics,2024,22(3):204-216.
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设计与筛选靶向PI3Kα的去氢骆驼蓬碱衍生物及其分子动力学验证
王昭志,贺宏吉,仲春红,卡迪热娅·艾克拉木,白静雅,王梅
(新疆医科大学 药学院,乌鲁木齐 830011)
摘要:
以PI3Kα作为靶蛋白,采用计算机辅助设计的方法优化去氢骆驼蓬碱结构,获得与靶蛋白结合力较高的化合物。在此基础上,利用分子对接,三维定量构效关系(3D-QSAR)和分子动力学技术验证了修饰化合物与靶蛋白的结合能力和稳定性。最后筛选出与靶标具有更好结合力的潜在去氢骆驼蓬碱结构衍生物。使用ACD/Percepta软件对去氢骆驼蓬碱的母核进行结构修饰,获得136 745个化合物的化合物库。通过Schrdinger软件从化合物库中依据MM/GBSA(分子力学广义玻恩表面积)筛选出结合能排在前三的化合物并使用3D-QSAR进行验证,最后通过分子动力学方法验证了三种结构衍生物,并预测了ADMET性质。通过软件设计、虚拟筛选、3D-QSAR模型构建和分子动力学模拟等一系列计算机辅助设计方法,获得了136 745种新的去氢骆驼蓬碱衍生物,评价了蛋白质结构复合物的稳定性,最终获得了3种结合能较高的化合物。其中,发现编号为37971的衍生物具有更好的3D-QSAR模型活性预测值与TPSA(拓扑极性表面积)值(87.84)和生物利用度(33.21%)。本研究结果为去氢骆驼蓬碱的结构修饰提供了设计思路,获得理论上与PI3Kα具有较好的靶向结合能力的化合物,通过分子对接和分子动力学验证,所获得的分子有望成为潜在的候选化合物,为进一步的实验验证奠定基础。
关键词:  去氢骆驼蓬碱  虚拟筛选  3D-QSAR  分子动力学  ADMET
DOI:10.12113/202304008
分类号:R914.2
文献标识码:A
基金项目:
Design and screening of dehydrogenated harmine derivatives targeting PI3Kα and their molecular dynamics validation
WANG Zhaozhi, HE Hongji, ZHONG Chunhong, KADIREYA Aikelamu, BAI Jingya,WANG Mei
(College of Pharmacy, Xinjiang Medical University, Urumqi 830011, China)
Abstract:
Using PI3Kα as the target protein, a computer-aided design method is used to optimize the structure of harmine and obtain compounds with high binding power to the target protein. On this basis, molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular dynamics techniques are used to verify the binding ability and stability of the modified compound to the target protein. Finally, potential harmine derivatives with better binding ability to the target are screened.Using ACD/Percepta software, structural modifications are performed on the mother nucleus of harmine, resulting in a compound library of 136 745 compounds. Schrdinger software is used to screen the compounds with MM/GBSA(Molecular mechanics generalized born surface area) binding energy ranking in the top three from the compound library, and 3D-QSAR is used to verify them. Finally, three structural derivatives are verified by molecular dynamics method, and the ADMET properties are predicted.Through a series of computer-aided design methods, including software design, 3D-QSAR,virtual screening and molecular dynamics simulation, 136 745 new derivatives of norharmaline are obtained, and the stability of the protein structure complex is evaluated, and finally 3 compounds with high binding energy are obtained. Among them, derivative No. 37971 is found to have better 3D-QSAR model activity prediction value,TPSA (topologically polar surface area) value (87.84) and bioavailability (33.21%). This study provides design ideas for the structural modification of norharmaline, which is obtained theoretically with PI3Kα Compounds with better target binding ability, the obtained molecules are expected to be potential candidate compounds through molecular docking and molecular dynamics validation, and lay the foundation for further experimental validation.
Key words:  Harmine  Virtual screening  3D-QSAR  Molecular dynamics  ADMET

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