取代喹啉类化合物抗菌活性的定量构效关系及分子设计

采用密度泛函理论(DFT)和逐步回归分析法对15种新合成的取代喹啉类化合物进行了定量构效关系(QSAR)研究. 在B3LYP/6-31G(d,p)水平上计算了取代喹啉的量子化学参数, 通过逐步多元回归分析筛选出影响抗菌活性的主要因素, 建立了定量构效关系方程, 并用留一法交叉分析了模型的稳定性及预测能力. 结果表明, C5的亲核电子密度fNC5及C9-N1的键级BC9-N1是影响喹啉类化合物抗金黄色葡萄球菌活性的主要因素, 所得模型对该类化合物抗菌活性有较好的预测效果. 同时基于QSAR研究结果设计了4个活性较高的新喹啉衍生物.     

咪唑啉衍生物缓蚀剂的定量构效关系及分子设计

采用量子化学密度泛函理论(DFT)及线性回归分析方法, 对十一烷基咪唑啉衍生物缓蚀剂抗H2S、CO2腐蚀性能进行了定量构效关系(QSAR)研究. 通过回归分析, 筛选出了影响缓蚀剂缓蚀性能的主要因素, 建立了QSAR模型, 并使用留一法交叉验证对模型的稳定性及预测能力进行了分析. 结果表明, 电子转移参数△N、咪唑环上非氢原子静电荷之和∑Qring及分子极化率α对咪唑啉类缓蚀剂的缓蚀性能有很大的贡献, 所得模型的拟合相关系数(R2)和交叉验证相关系数(q2)分别为0.924 和0.917, 模型对此类缓蚀剂抗H2S、CO2腐蚀性能具有较好的预测效果. 应用QSAR研究结果进行了分子设计, 在理论上提出了一些具有较高抗H2S、CO2腐蚀性能的新型咪唑啉衍生物, 为实验工作者合成新型缓蚀剂提供理论参考.     

Molecular overtones as local modes

The apparent simplicity of polyatomic overtone spectra and the conceptual utility of local modes are considered. The form and basis-set-dependence of the dipole moment operator are discussed and a criterion given for overtone spectra to be well described within a local mode picture. Caution is needed in making dynamical inferences based on agreement between overtone and local mode line positions.     

螺环吲哚类MDM2抑制剂的分子对接、定量构效关系和分子动力学模拟

采用分子对接、三维定量构效关系(3D-QSAR)和分子动力学方法研究了21个螺环吲哚类化合物与MDM2蛋白的相互作用, 并建立了相关预测模型. 比较分子场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA)模型的交互验证相关系数q²分别为0.573 和0.651, 非交互验证相关系数r²分别为0.948和0.980. 分子对接得到的结合模式与分子动力学模拟得到的结果一致, 结合模式表明该类螺环吲哚化合物主要通过疏水相互作用和氢键与MDM2结合. 基于上述相互作用模型设计并合成了6个新结构螺环吲哚化合物, 并在MDM2高表达的前列腺癌LNCaP细胞株上测定其活性, 结果表明化合物5, 6的半数抑制浓度均低于1μg·mL^-1, 可作为新的抗肿瘤药物先导化合物进一步深入研究. 本研究对以MDM2为靶点的新结构螺环吲哚类抑制剂的开发提供了理论和实验依据.     

五元杂环并嘧啶类胸苷酸合成酶抑制剂的构效关系和分子对接

用比较分子场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA)研究了38个五元杂环并嘧啶衍生物类胸苷酸合成酶抑制剂的三维定量构效关系(3D-QSAR), 建立了相关预测模型. CoMFA和CoMSIA模型的交互验证相关系数q²分别为0.662和0.672、非交互验证相关系数R²分别为0.921和0.884、外部交互验证相关系数Q_ext²分别为0.85和0.81. 分子对接得到的结合模式与三维定量构效关系得到的结果一致. 结果表明这两种模型都具有良好的预测能力, 可应用于指导化合物的设计和结构修饰, 为进一步设计新型胸苷酸合成酶抑制剂提供了理论依据.     

QSAR and Molecular Docking Studies of Pyrimidine-Coumarin-Triazole Conjugates as Prospective Anti-Breast Cancer Agents

Cancer is a life-threatening disease and is the second leading cause of death worldwide. Although many drugs are available for the treatment of cancer, survival outcomes are very low. Hence, rapid development of newer anticancer agents is a prime focus of the medicinal chemistry community. Since the recent past, computational methods have been extensively employed for accelerating the drug discovery process. In view of this, in the present study we performed 2D-QSAR (Quantitative Structure-Activity Relationship) analysis of a series of compounds reported with potential anticancer activity against breast cancer cell line MCF7 using QSARINS software. The best four models exhibited a r² value of 0.99. From the generated QSAR equations, a series of pyrimidine-coumarin-triazole conjugates were designed and their MCF7 cell inhibitory activities were predicted using the QSAR equations. Furthermore, molecular docking studies were carried out for the designed compounds using AutoDock Vina against dihydrofolate reductase (DHFR), colchicine and vinblastine binding sites of tubulin, the key enzyme targets in breast cancer. The most active compounds identified through these computational studies will be useful for synthesizing and testing them as prospective novel anti-breast cancer agents.     

含磷嘧啶类CDK9抑制剂的分子对接、3D-QSAR和分子动力学模拟

选取64个具有潜力的含磷嘧啶类细胞周期依赖性蛋白激酶(CDK9)小分子抑制剂,采用分子对接方法研究了该类小分子与CDK9的结合作用,结果表明,分子构象、氢键形成、疏水性和氨基酸残基Cys106在此类抑制剂与CDK9的结合过程中具有重要作用.在配体叠合的基础上,运用比较分子力场分析(Co MFA)、比较分子相似性指数分析(Co MSIA)和Topomer Co MFA(T-COMFA)研究了分子结构与抑制活性的关系,发现由训练集立体场、静电场和疏水场组合的Co MSIA模型为最优模型,其内部交叉验证相关系数(Q2=0.557)、非交叉验证相关系数(R2=0.959)和外部预测相关系数(r2=0.863)具有统计学意义,该模型的三维等值线图直观显示了化合物的活性与其三维结构的关系.根据这些结果设计了10个具有新结构的含磷嘧啶类化合物,分子对接和分子动力学模拟结果表明,新化合物和CDK9的结合模式与原化合物64相同,自由能分析从理论上证明了新化合物64d的CDK9抑制活性优于化合物64,并且显示含磷基团与残基Asp109的静电场能在化合物与CDK9作用过程中有重要作用.     

3D QSAR Modeling and Molecular Docking Studies on a Series of Triazole Analogues as Antibacterial Agents

The 3D QSAR analysis using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques is performed on novel nalidixic acid based 1,2,4-triazole derivatives suggested earlier as antibacterial agents. The CoMFA and CoMSIA models employed for a training set of 28 compounds gives reliable values of Q² (0.53 and 0.52, respectively) and R² (0.79 and 0.85, respectively). The contour maps produced by the CoMFA and CoMSIA models are used to determine a three-dimensional quantitative structure-activity relationship. Based on the 3D QSAR contours new molecules with high predicted activities are designed. In addition, surflex-docking is performed to confirm the stability of predicted molecules in the receptor.     

Molecular Docking and 3D QSAR Research of Indolocarbazole Series as Cyclin-Dependent Kinase Inhibitors

Fifty indolocarbazole series as cyclin-dependent kinase inhibitors (CDKs) are used to establish a threedimensional quantitative structure-activity relationship (3D QSAR) model based on docking conformations resulting from the Topomer comparative molecular field analysis (Topomer CoMFA). The statistic parameters show that the cross-validation (q²), the multiple correlation coefficient of fitting (r²), and external validation statistic (Q_ext²) are 0.953, 0.968, and 0.954, respectively. It is demonstrated that this Topomer CoMFA model has good stability and prediction ability. The methodology of the fragment-based drug design (FBDD) was also used to virtually screen new CDKs by the Topomer Search technology. Four similar substitutional groups selected from the ZINC database were added to the basic scaffold. As a result, 18 new CDKs with high activities were obtained. The template molecule and new designed compounds are used to study the binding relationship between the ligands and the receptor protein with Surflex-Dock. The docking results suggest good binding interactions of the designed compounds with protein. There are several hydrogen bondings between CDKs with amino acid residues of LYS33, LYS89, ASP86, LEU83, GLU81.     

多肽定量构效关系与分子设计

综述了多肽定量构效关系和计算机辅助多肽分子设计方法的最新进展,重点介绍了多肽定量构效关系研究中的化学结构定量描述符和建立数学模型的统计方法,并对模拟肽学和虚拟组合多肽库在多肽分子设计中的应用进行了简要的论述.     

3C-like蛋白酶抑制剂的构效关系、分子对接和分子动力学

3C-like蛋白酶是中东呼吸综合征冠状病毒（MERS-CoV）等其它冠状病毒的繁殖过程中极为重要的蛋白酶。它已成为人类在抗冠状病毒领域中的研究热点。本文基于计算生物学方法对与MERS-CoV同属的蝙蝠冠状病毒HKU4（HKU4-CoV）的43个肽类3C-like蛋白酶抑制剂分子,建立三维定量构效关系（3D-QSAR）模型。在基于配体叠合的基础上,发现比较分子相似性指数分析法（CoMSIA）中的四个场组合（位阻场、静电场、氢键供体场与氢键受体场）为最优的模型（Q²=0.522,R_ncv²=0.996,R_pre²=0.904;Q²：交叉验证相关系数,R_ncv²：非交叉验证相关系数,R_pre²：验证集分子的预测值相关系数）,并借助该模型通过分子对接（docking）与分子动力学（MD）方法阐明了配受体结合作用。实验结果表明：（1）基于最优的CoMSIA模型基础上的三维等势图形象地说明了分子基团的位阻作用、静电作用、氢键供体与氢键受体作用对分子生物活性的影响;（2）分子对接研究结果显示了疏水性以及结晶水、氨基酸His166和Glu169在配体和受体结合过程中产生重要作用;（3）分子动力学模拟进一步验证了分子对接模型的可靠性,并发现了两个新的关键氨基酸Ser24与Gln192,它们与配体产生了两个较强的氢键。此外,根据这些结果,一些新的具有潜在抑制活性的肽类化合物作为3C-like蛋白酶抑制剂被获得。以上结果能够帮助深入了解3C-like蛋白酶与肽类抑制剂的作用机理,并且能够为今后的抗MERS-CoV药物设计提供有价值的参考。     

一种新的分子拓扑指数及其在QSPR/QSAR研究中的应用

通过引入量子数、键参数,认为分子的性质与其中各原子的电负性、价电子数、成键电子数、价层主量子数及各化学键的键长有关,提出了一种新的分子拓扑指数mAY.采用该拓扑指数对饱和烷烃、烷基苯、烷氧氯硅烷、卤代苯、含氮杂环化合物、碱金属卤化物及卤化锡的性质/活性进行了相关关系的研究.结果表明,mAY与有机物和无机物的性质/活性间具有良好的相关性.     

Molecular transformations of unsaturated thiacrown ethers

Unsaturated thiacrown ethers with 15, 18, and 21 members were oxidized to sulfoxides by the reaction with m-CPBA. The reaction with t-BuOCl at -20 degrees C also afforded sulfoxides, whereas the reaction at room temperature yielded cis-trans isomerized compounds. The cis-trans isomerized compound was also obtained by the photochemical reaction or by the reaction with NCS and NCP. Meanwhile, the reaction with NBS and NBP provided an acetal via 1,2-bridged bromonium intermediate.     

Molecular Lipophilicity Potential,a tool in 3D QSAR: Method and applications

Summary A new method is presented to calculate the Molecular Lipophilicity Potential (MLP). The method is validated by showing that the MLP thus generated on the solvent-accessible surface can be used to back-calculate log P. Because the MLP is shown to be sensitive to conformational effects, the MLP/log P relation is best sought by taking all conformers into account. The MLP method presented here can be used as a third field in CoMFA studies, as illustrated with two series of ₁ ligands. In the first series, the steric, electrostatic and lipophilic fields are highly intercorrelated, and taken separately yield comparable models. In the second series of ligands, the best model is obtained with the lipophilic field alone, allowing insights into ligand-receptor interactions.     

3-吡啶基醚类化合物的分子全息QSAR研究

采用分子全息定量构效关系(HQSAR, hologram quantitative structure-activity relationship)方法, 研究了28个3-吡啶基醚类化合物对乙酰胆碱α4β2受体的亲和性与它们的分子结构之间的关系, 讨论了分子碎片大小、分子碎片亚结构类型以及分子全息长度对QSAR的影响, 得到了较好的HQSAR模型, 模型的交叉验证系数平方q²＝0.670, 非交叉相关系数平方r²＝0.965, 偏差S＝0.093. 利用HQSAR的颜色编码, 对化合物中不同基团对亲和活性的影响进行了讨论, 对新配体的合成具有一定的指导作用.     

N-取代马来酰亚胺类hMGL抑制剂的3D-QSAR、分子对接和分子动力学研究

本文通过三维定量构效关系(3D-QSAR)建模、分子对接和分子动力学模拟,探讨了41个N-取代马来酰亚胺类衍生物与人单酰甘油脂肪酶(hMGL)的相互作用,并构建了相关模型。其中,比较分子力场分析模型(CoMFA、q₂ ^{= 0. 5}41、r₂ ^{= 0. 9}72)和比较分子相似性指数分析模型(CoMSIA、q₂ ^{= 0. 5}88、r₂ ^{= 0. 9}19)具有较好的预测能力。QSAR模型等势图阐明了该系列化合物生物活性与结构的关系,并依此设计了系列衍生物。采用分子对接和分子动力学模拟探讨了高活性化合物36、46与hMGL(PDB ID: 3PE6)的结合模式和稳定性,结果表明二者主要通过氢键和疏水相互作用与hMGL结合并且形成了稳定的复合物。随后对pIC₅₀预测值优于文献报道中最高活性化合物36的8个衍生物进行分子对接和ADMET预测,选择2个衍生物进行分子动力学模拟,结果表明2个衍生物分别与hMGL形成的复合物结合构象稳定。本研究为新型N-取代马来酰亚胺类单酰甘油脂肪酶抑制剂的开发提供了理论依据。