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  

Design and screening of dehydrogenated harmine derivatives targeting PI3Kαand their molecular dynamics validation

作　　者：王昭志 贺宏吉 仲春红 卡迪热娅·艾克拉木 白静雅 王梅[1] WANG Zhaozhi;HE Hongji;ZHONG Chunhong;KADIREYA Aikelamu;BAI Jingya;WANG Mei(College of Pharmacy,Xinjiang Medical University,Urumqi 830011,China)

机构地区：[1]新疆医科大学药学院,乌鲁木齐830011

出　　处：《生物信息学》2024年第3期204-216,共13页Chinese Journal of Bioinformatics

基　　金：国家自然科学基金项目(No.81760637)

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136745个化合物的化合物库。通过Schr9dinger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136745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。Using PI3Kαas 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 136745 compounds.Schrödinger 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,136745 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 PI3KαCompounds 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.

关 键 词：去氢骆驼蓬碱 虚拟筛选 3D-QSAR 分子动力学 ADMET 

分 类 号：R914.2[医药卫生—药物化学]