A series of 46 dihydro-alkoxy-benzyl-oxopyrimidines （DABOs）, a class of highly potent non-nucleoside reverse transcriptase inhibitors （NNRTIs）, was studied by molecular docking followed by comparative molecular fi...A series of 46 dihydro-alkoxy-benzyl-oxopyrimidines （DABOs）, a class of highly potent non-nucleoside reverse transcriptase inhibitors （NNRTIs）, was studied by molecular docking followed by comparative molecular field analysis （CoMFA） and comparative molecular similarity index analysis （CoMSIA）. The results showed that the H-bonding interactions between the C=O and NH of the pyrimidine ring and Lys101, hydrophobic interactions between R, R1, X sites of ligands and neighboring amino acid residuals, and the electrostatic interactions between ligands and His235 and Lys101 residues were the dominant factors affecting the binding affinities. Based on an optimal docking conformation, 3D-QSAR models of 46 DABO derivatives were developed. The r^2 and cross-validated r^2 （q^2） of an optimal CoMSIA model were 0.862 and 0.532, respectively. Based on the QSAR studies, 9 new compounds were designed by the method of LeapFrog. The binding energies and docking scores （GScore） of 9 new compounds were better than that of a template molecule with the highest observed activity. The results showed that the molecular designs of DABOs should be focused on the hydrophobic interactions with the bottom of the binding pocket as well as van der Waals interactions with the entrance of binding pocket.展开更多
泛素-蛋白酶体在真核生物的抗原呈递、细胞周期调控和转录因子激活等生理过程中发挥着极为重要的作用,其核心就是蛋白酶体对底物的选择性酶切作用,因此对选择性酶切位点的预测一直是计算生物学的一个重点研究内容.针对现有酶切位点预测...泛素-蛋白酶体在真核生物的抗原呈递、细胞周期调控和转录因子激活等生理过程中发挥着极为重要的作用,其核心就是蛋白酶体对底物的选择性酶切作用,因此对选择性酶切位点的预测一直是计算生物学的一个重点研究内容.针对现有酶切位点预测方法的非线性和物理意义不明确等问题,借鉴定量构效关系研究方法,采用基于氨基酸物理化学性质的描述子——VHSE(Principal component score vector of hydrophobic,steric,and electronic properties)对收集的2650个MHC-I配体的源蛋白序列进行了结构表征,在此基础上利用支持向量机建立了蛋白酶体酶切位点的预测模型,其最优线性模型的灵敏度(Sensitivity)、特异性(Specificity)、接受者操作特征曲线下面积(area under receiver operatingcharacteristics curve,AUC)和马休斯相关系数(Matthews coefficient of correlation,MCC)分别为90.18%,69.63%,0.8797和0.6131.模型分析结果表明:影响酶切位点选择性的氨基酸性质由大到小依次为:疏水性、电性和立体特征;P9,P8,P4,P1,P3',P4'和P5'位氨基酸对酶切位点的选择有重要影响,研究亦显示酶切位点上游P1位和下游P1'～P5'的"疏水势差"有利于蛋白酶体的切割作用.展开更多
基金国家自然科学基金青年基金项目“基于本体方法的我国上市甲乙肝疫苗相关不良反应数据挖掘与建模分析”(61801067)重庆市教育委员会科学技术研究重点项目“卡介苗两种用途下相应不良反应信息的本体化表征与建模分析”(KJZD-K202000603)+4 种基金中国医学科学院中央级公益性科研院所基本科研业务费专项资金资助,“国家卫生健康委员会肺脏免疫性疾病诊治重点实验室”建设项目(2019PT320003)University of Michigan Medical School Global Reach FundMichigan Medicine-Peking University Health Sciences Center Joint Institute for Clinical and Translational Research“Systemic Investigation of the Microbiome-host interactions in H.pylori-associated Gastric Cancer Patients”(U063430,BMU2019JI010)国家重点研发计划精准医学研究专项“疾病表型组-实验组学数据分析、注释与整合”(2017YFC0908404)中国医学科学院医学与健康科技创新工程项目“生物医学本体支持的通用数据元素表示和应用系统建设”(2018-I2M-AI-009)。
基金Supported by the Fundamental Research Funds for the Central Universities (No. CDJZR10230010)the Third Stage Training of 211 Project (No. S-09104)
文摘A series of 46 dihydro-alkoxy-benzyl-oxopyrimidines （DABOs）, a class of highly potent non-nucleoside reverse transcriptase inhibitors （NNRTIs）, was studied by molecular docking followed by comparative molecular field analysis （CoMFA） and comparative molecular similarity index analysis （CoMSIA）. The results showed that the H-bonding interactions between the C=O and NH of the pyrimidine ring and Lys101, hydrophobic interactions between R, R1, X sites of ligands and neighboring amino acid residuals, and the electrostatic interactions between ligands and His235 and Lys101 residues were the dominant factors affecting the binding affinities. Based on an optimal docking conformation, 3D-QSAR models of 46 DABO derivatives were developed. The r^2 and cross-validated r^2 （q^2） of an optimal CoMSIA model were 0.862 and 0.532, respectively. Based on the QSAR studies, 9 new compounds were designed by the method of LeapFrog. The binding energies and docking scores （GScore） of 9 new compounds were better than that of a template molecule with the highest observed activity. The results showed that the molecular designs of DABOs should be focused on the hydrophobic interactions with the bottom of the binding pocket as well as van der Waals interactions with the entrance of binding pocket.
文摘泛素-蛋白酶体在真核生物的抗原呈递、细胞周期调控和转录因子激活等生理过程中发挥着极为重要的作用,其核心就是蛋白酶体对底物的选择性酶切作用,因此对选择性酶切位点的预测一直是计算生物学的一个重点研究内容.针对现有酶切位点预测方法的非线性和物理意义不明确等问题,借鉴定量构效关系研究方法,采用基于氨基酸物理化学性质的描述子——VHSE(Principal component score vector of hydrophobic,steric,and electronic properties)对收集的2650个MHC-I配体的源蛋白序列进行了结构表征,在此基础上利用支持向量机建立了蛋白酶体酶切位点的预测模型,其最优线性模型的灵敏度(Sensitivity)、特异性(Specificity)、接受者操作特征曲线下面积(area under receiver operatingcharacteristics curve,AUC)和马休斯相关系数(Matthews coefficient of correlation,MCC)分别为90.18%,69.63%,0.8797和0.6131.模型分析结果表明:影响酶切位点选择性的氨基酸性质由大到小依次为:疏水性、电性和立体特征;P9,P8,P4,P1,P3',P4'和P5'位氨基酸对酶切位点的选择有重要影响,研究亦显示酶切位点上游P1位和下游P1'～P5'的"疏水势差"有利于蛋白酶体的切割作用.
