3D-QSAR Study on Apicidin Inhibit Histone Deacetylase

For Histone Deacetylase (HDAC) Inhibitor, four 3D-QSAR models for four types of different activities, were constructed.The cross-valldated q^2 value of CoMFA Model 1 is 0.624 and the noncross-validated r2 value is 0.939. The cross-validated q^2 value of Model 2 for training set is 0.652 and the noncross-validated r^2 value is 0.963. The cross-validated q^2 value for Model 3 is 0.713, with noncross-validated r^2 value 0.947. The crossvalidated q2 value for Model 4 is 0.566 with noncross-validated r^2 value 0.959. Their predicted abilities were validated by different test sets which did not include in training set. Then the relationship between substituents and activities was analyzed by using these models and the main influence elements in different positions (positions 8 and 14) were found. The polar donor electron group of position 8 could increase the activity of inhibition of HDAC, because it could form chelation with the catalytic Zn. Suitable bulk and positive groups at position 14 are favorable to anti-HDAC activity. These models could web interpret the relationship between inhibition activity and apicidin structure affording us important information for structurebased drug design.     

Novel Sulfonamide Derivatives as Inhibitors of Histone Deacetylase

Inhibition of the enzyme histone deacetylase (HDAC) is emerging as a novel approach to the treatment of cancer. A series of novel sulfonamide derivatives were synthesized and evaluated for their ability to inhibit human HDAC. Compounds were identified which are potent enzyme inhibitors, with IC₅₀ values in the low nanomolar range against enzyme obtained from HeLa cell extracts, and with antiproliferative effects in cell culture. Extensive characterization of the structure–activity relationships of this series identified key requirements for activity. These include the direction of the sulfonamide bond and substitution patterns on the central phenyl ring. The alkyl spacer between the aromatic head group and the sulfonamide functionality also influenced the HDAC inhibitory activity. One of these compounds, m 11.1 , also designated PXD101, has entered clinical trials for solid tumors and haematological malignancies.     

3D-QSAR Studies on the Anti-tumor Activity of N-Aryl-salicylamide Derivatives

In the present work, comparative molecular field analysis(CoMFA) techniques were used to perform three-dimensional quantitative structure-activity relationship(3 D-QSAR) studies on the anti-tumor activity(pHi, i = 1, 2, 3, 4) of N-aryl-salicylamide derivatives against four cancer cell lines, including A549, MCF-7, SGC-7901, and Bel-7402. 12 compounds were randomly selected as the training set to establish the prediction models, which were verified by the test set of 5 compounds containing template molecule. The contributions of steric and electrostatic fields to pH1, pH2, pH_3, and pH_4were 23.8% and 76.2%, 20.1% and 79.9%, 18.7% and 81.3%, and 14.3% and 85.7%, respectively. The cross-validation(Rcv2) and non-cross-validation coefficients(R2) were 0.826 and 0.963 for pH1, 0.867 and 0.974 for pH2, 0.941 and 0.989 for pH_3, and 0.797 and 0.961 for pH_4, respectively. The CoMFA models were then used to predict the activities of the compounds, and it was found that the models had strong stability and good predictability. Based on the CoMFA contour maps, some key structural factors responsible for the anticancer activity of the series of compounds were revealed. The results provide some useful theoretical references for understanding the mechanism of action, designing new N-aryl-salicylamide derivatives with high anti-tumor activity, and predicting their activities.     

胆固醇酯转运蛋白抑制剂的3D-QSAR模型

利用VolSurf参数和比较分子场分析(CoMFA)方法对N,N-二取代三氟-3-氨基-2-丙醇衍生物类胆固醇酯转运蛋白抑制剂进行了三维定量构效关系(3D-QSAR)模型研究, 均得到较好的结果, 训练集模型具有良好的预测能力. VolSurf参数分析表明抑制活性高的分子必须具有合适的亲水性、多的氢键给体和少的氢键受体; 在一定范围内, 分子量大、表面光滑且非球性高的分子抑制活性高; 高疏水性以及质量中心与疏水区中心的高不平衡性对活性是不利因素. CoMFA结果表明, 立体作用对活性的影响较静电作用稍强, N-苯基取代基苯氧基的间位体积大且正电性强的基团对活性有利, N-苄基取代基的间位体积大且合适的电负性对活性有利, 而苄基的对位立体位阻的增加则对活性不利. VolSurf参数提供了分子整体性质信息, CoMFA提供了取代基信息, 两者互为补充, 对该类抑制剂新化合物的设计具有指导意义.     

新型苯甲酰胺类HDAC抑制剂的合成及其抗肿瘤活性

以MS-275为先导化合物,设计并合成了7个新型苯甲酰胺类化合物（6a~6c, 14a, 14b, 15a和18）,其结构经¹H NMR和ESI-MS表征。采用MTT法测定了6a~6c, 14a, 14b, 15a和18对人急性白血病细胞(HL60)和人乳腺癌细胞(MCF-7)的体外抗肿瘤细胞增殖活性。结果表明：N-(2-氨基苯)-3-［4-(吡啶-3-基)嘧啶-2-氨基］己酰胺（6a）, N-(2-氨基苯)-4-【3-{4-［(二乙胺基)甲基］苯基}丙烯酰】苯甲酰胺（14a）和N-(2-氨基苯)-4-［3-(吡啶-3-基)丙烯酰］丙酰胺(18）的抑制活性较好,其GI₅₀依次为5.72 μmol·L^-1, 6.91 μmol·L^-1, 7.11 μmol·L^-1和3.46 μmol·L^-1, 4.12 μmol·L^-1, 3.97 μmol·L^-1,优于MS-275(7.88 μmol·L^-1和4.49 μmol·L^-1)。     

家蝇与大鼠GABA受体抑制剂的药效团模型及其3D-QSAR研究

采用DISCOtech方法,用7个大鼠γ-氨基丁酸(GABA)A受体抑制剂和11个家蝇GABAA受体抑制剂分别建立了其药效团模型;用CoMFA方法建立了22个大鼠GABAA受体抑制剂和29个家蝇GABAA受体抑制剂的3D-QSAR模型,模型的交叉验证相关系数分别为0.526和0.679,验证了药效团模型的合理性,为设计更高活性和更高选择性的化合物提供了参考     

Target Design of Novel Histone Deacetylase 6 Selective Inhibitors with 2-Mercaptoquinazolinone as the Cap Moiety

Epigenetic alterations found in all human cancers are promising targets for anticancer therapy. In this sense, histone deacetylase inhibitors (HDACIs) are interesting anticancer agents that play an important role in the epigenetic regulation of cancer cells. Here, we report 15 novel hydroxamic acid-based histone deacetylase inhibitors with quinazolinone core structures. Five compounds exhibited antiproliferative activity with IC₅₀ values of 3.4–37.8 µM. Compound 8 with a 2-mercaptoquinazolinone cap moiety displayed the highest antiproliferative efficacy against MCF-7 cells. For the HDAC6 target selectivity study, compound 8 displayed an IC₅₀ value of 2.3 µM, which is 29.3 times higher than those of HDAC3, HDAC4, HDAC8, and HDAC11. Western blot assay proved that compound 8 strongly inhibited tubulin acetylation, a substrate of HDAC6. Compound 8 also displayed stronger inhibition activity against HDAC11 than the control drug Belinostat. The inhibitory mechanism of action of compound 8 on HDAC enzymes was then explored using molecular docking study. The data revealed a high binding affinity (−7.92 kcal/mol) of compound 8 toward HDAC6. In addition, dock pose analysis also proved that compound 8 might serve as a potent inhibitor of HDAC11.     

含呋喃环双酰肼类衍生物的合成、杀虫活性及3D-QSAR研究

为发现新的昆虫生长调节剂,经单取代苯基呋喃甲酰氯与取代苯甲酰肼反应得到22个未见文献报道的含呋喃环双酰肼类化合物,其结构均通过了IR,1HNMR和元素分析确认.初步生测结果表明,所有目标化合物对豆蚜(Aphisfabae)均有活性,部分目标化合物表现出较好或中等的杀幼虫活性.化合物Ia,Ib和Ic在药剂浓度为0.05%时,对豆蚜的死亡抑制率分别为81.8%,58.4%和52.2%,其中化合物Ia对若蚜的蜕皮和成蚜产雌能力具有一定的抑制作用.而大部分目标化合物在药剂浓度为0.1%,0.05%和0.001%时,对3龄粘虫(Mythimna separate)、棉红蜘蛛(Tetranchus urticae)和尖音淡色库蚊(Culex pipiens pallens)幼虫杀虫活性不明显.采用比较分子力场分析(CoMFA)方法,对22个化合物的杀蚜虫活性进行三维定量构效关系(3D-QSAR)研究.在CoMFA研究中,考察了不同力场和电荷下网格点步长对统计结果的影响.建立了三维定量构效关系CoMFA模型(q2=0.518,r2=0.936).CoMFA模型的立体场、静电场三维等值线图不仅直观地解释了结构与活性的关系,而且为后续优化该系列化合物提供了理论依据.     

The Effect of Vicinal Difluorination on the Conformation and Potency of Histone Deacetylase Inhibitors

Histone deacetylase enzymes (HDACs) are potential targets for the treatment of cancer and other diseases, but it is challenging to design isoform-selective agents. In this work, we created new analogs of two established but non-selective HDAC inhibitors. We decorated the central linker chains of the molecules with specifically positioned fluorine atoms in order to control the molecular conformations. The fluorinated analogs were screened against a panel of 11 HDAC isoforms, and minor differences in isoform selectivity patterns were observed.     

A Sensitive Electrochemical Biosensor for Detection of Histone Deacetylase Activity Using an Acetylated Peptide

A sensitive electrochemical biosensor was developed for activity detection of histone deacetylase sirtuin2 (SIRT2) using an acetylated peptide substrate. This substrate could be recognized by anti‐acetylated peptide antibody, which could be detected using secondary antibody conjugated alkaline phosphatase which provided an amplified electrochemical signal. In the presence of SIRT2, the substrate was deacetylated, resulting in a decreased electrochemical signal that was correlated to the concentration of SIRT2. Under optimized conditions, the biosensor exhibited a wide linear range from 1 nM to 500 nM with a detection limit of 0.1 nM. The proposed biosensor was also used for detection of SIRT2 inhibitor.     

磺胺基羟肟酸类HDAC抑制剂三维定量构效关系

组蛋白去乙酰化酶(HDAC)对染色质分布和基因调节起着重要的作用,也是治疗癌症和其它疾病的新靶点.羟肟酸类抑制剂是目前研究最多的组蛋白去乙酰化酶抑制剂.应用比较分子力场(CoMFA)法对一系列磺胺基羟肟酸类HDAC抑制剂进行了结构活性关系研究,得到的模型具有较高的交叉验证系数(q²=0.704).并在此基础上,建立了非交叉验证的偏最小二乘分析(PLS)模型.用该模型对随机选择的6个化合物组成的测试集进行了预测,得到了令人满意的结果,所建模型具有良好的预测能力.本研究对于设计高活性的HDAC抑制剂及抗癌药物都有指导意义.     

2,4-二氨基嘧啶类FAK抑制剂的3D-QSAR研究

摘要 本文选取42个2,4-二氨基嘧啶类FAK小分子抑制剂,分别以比较分子场分析法（CoMFA）与相似性指数分析法（CoMSIA）构建3D-QSAR模型,评价模板分子、公共骨架点、最小能量优化参数、分子构象等因素对模型优化的影响。分析最优模型中立体场、静电场以及氢键等因素对抑制剂活性的影响,并应用分子对接分析该类抑制剂与FAK蛋白的相互作用。结果表明选择16号化合物作为模板分子,骨架A作为公共骨架点,最小能量优化参数中电荷、最大迭代系数、最低能量限定值分别为MMFF94、1000、0.01 Kcal/mol时所构建的模型最优。以CoMFA和CoMSIA构建的3D-QSAR模型的交叉验证系数（q2）分别为0.666和0.736,非交叉验证系数（R2）分别为0.990和0.989,表明此模型具有良好的预测能力。分子对接分析显示,其与FAK的氨基酸残基CYS502、ASP564形成了重要的氢键作用,并与周围残基形成了较强的疏水作用。通过3D-QSAR的构建与分子对接分析,可指导2,4-二氨基嘧啶类FAK小分子抑制剂的进一步结构优化设计。     

Docking and 3D-QSAR Analysis on a Series of Pyridone-based EZH2 Inhibitors

Enhancer of Zeste homolog 2(EZH2) is closely correlated with malignant tumor and regarded as a promising target to treat B-cell lymphoma. In our research, the molecular docking and three-dimensional quantitative structure-activity relationships(3D-QSAR) studies were performed on a series of pyridone-based EZH2 compounds. Molecular docking allowed us to study the critical interactions at the binding site of EZH2 protein with inhibitors and identify the practical conformations of ligands in binding pocket. Moreover, the docking-based alignment was applied to derive the reliable 3D-QSAR models. Comparative molecular field analysis(CoMFA) and comparative molecular similarity indices analysis(CoMSIA) provided available ability of visualization. All the derived 3D-QSAR models were considered to be statistically significant with respect to the internal and external validation parameters. For the CoMFA model, q~2 = 0.649, r~2 = 0.961 and r~2 pred = 0.877. For the CoMSIA model, q~2 = 0.733, r~2 = 0.980 and r~2 pred = 0.848. With the above arguments, we extracted the correlation between the biological activity and structure. Based on the binding interaction and 3D contour maps, several new potential inhibitors with higher biological activity predicted were designed, which still awaited experimental validation. These theoretical conclusions could be helpful for further research and exploring potential EZH2 inhibitors.     

Histone Deacetylase Inhibitory Activity and Antiproliferative Potential of New [6]-Shogaol Derivatives

Twenty newly synthesized derivatives of [6]-shogaol (4) were tested for inhibitory activity against histone deacetylases. All derivatives showed moderate to good histone deacetylase inhibition at 100 µM with a slightly lower potency than the lead compound. Most potent inhibitors among the derivatives were the pyrazole products, 5j and 5k, and the Michael adduct with pyridine 4c and benzothiazole 4d, with IC₅₀ values of 51, 65, 61 and 60 µM, respectively. They were further evaluated for isoform selectivity via a molecular docking study. Compound 4d showed the best selectivity towards HDAC3, whereas compound 5k showed the best selectivity towards HDAC2. The potential derivatives were tested on five cancer cell lines, including human cervical cancer (HeLa), human colon cancer (HCT116), human breast adenocarcinoma cancer (MCF-7), and cholangiocarcinoma (KKU100 and KKU-M213B) cells with MTT-based assay. The most active histone deacetylase inhibitor 5j exhibited the best antiproliferative activity against HeLa, HCT116, and MCF-7, with IC₅₀ values of 8.09, 9.65 and 11.57 µM, respectively, and a selective binding to HDAC1 based on molecular docking experiments. The results suggest that these compounds can be putative candidates for the development of anticancer drugs via inhibiting HDACs.     

3D-QSAR Studies of the Pteridine Analogues as iNOS Inhibitors

Inducible nitric oxide synthase(iNOS), which can produce nitric oxide(NO) in the induction of cytokines and other factors, has an important impact onthe physiological functions of the body for the transmission of information. However,continuous generation of NOwill produce a lot of great damages to organisms. Therefore, iNOS inhibitors with good inhibitory activity and selectivity have beenimportant means of treating a variety of diseases. Based on the public-alignment of pteridine, 3D-QSAR(Three-Dimensional Quantitative Structure-Activity Relationship) models of pteridine analogues as iNOS inhibitors were established by the 3D-QSAR protocol of Discovery Studio 3.0. Pteridine molecules divided in different groups obtained four approximate models, indicating good stability of such models, in which A3 is preferable(q~2 = 0.672, r~2 = 0.996, r_(pred)~2 . = 0.888, q~2 denotes the cross-validation coefficient, r~2 denotes the non-cross-validation coefficient). This study should be significant for the future structure design and modification of pteridine analogues as iNOS inhibitors.     

Construction of 4D-QSAR Models for Use in the Design of Novel p38-MAPK Inhibitors

The p38-mitogen-activated protein kinase (p38-MAPK) plays a key role in lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) release during the inflammatory process, emerging as an attractive target for new anti-inflammatory agents. Four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis [Hopfinger et al., J. Am. Chem. Soc., 119 (1997) 10509] was applied to a series of 33 (a training set of 28 and a test set of 5) pyridinyl-imidazole and pyrimidinyl-imidazole inhibitors of p38-MAPK, with IC50 ranging from 0.11 to 2100 nM [Liverton et al., J. Med. Chem., 42 (1999) 2180]. Five thousand conformations of each analogue were sampled from a molecular dynamics simulation (MDS) during 50 ps at a constant temperature of 303 K. Each conformation was placed in a 2 angstroms grid cell lattice for each of three trial alignments. 4D-QSAR models were constructed by genetic algorithm (GA) optimization and partial least squares (PLS) fitting, and evaluated by leave-one-out cross-validation technique. In the best models, with three to six terms, the adjusted cross-validated squared correlation coefficients, Q2adj, ranged from 0.67 to 0.85. Model D (Q2adj = 0.84) was identified as the most robust model from alignment 1, and it is representative of the other best models. This model encompasses new molecular regions as containing pharmacophore sites, such as the amino-benzyl moiety of pyrimidine analogs and the N1-substituent in the imidazole ring. These regions of the ligands should be further explored to identify better anti-inflammatory inhibitors of p38-MAPK.     

抗癌性喹唑啉类二氢叶酸还原酶抑制剂三维定量构效关系

在对一系列抗癌性7,8-二烃基-1,3-二氨基吡咯-[3,2-f]喹唑啉类二氢叶酸还原酶抑制剂的二维定量构效关系（2D—QSAa）研究基础上,应用比较分子场分析法对该类配合物进行了三维定量构效关系（3D—QSAR）研究．建立了具有良好的统计学性能及预报能力的3D．QSAR模型,非交叉验证相关系数为0．993,交叉验证相关系数为0．619,估算的标准误差0．208,统计方差比193．4．该模型表明立体场因素的影响比静电场因素大很多,此结果与我们已经报道的2D—QSAR模型结果相一致．然而,3D—QSAR模型提供了可视化的立体场、静电场因素对活性的影响．3D—QSAR研究对实验上提出的二氢叶酸还原酶与药物分子的疏水键合作用机理得到了进一步的理论解释．