CDK4与靛玉红及其衍生物复合物结构的模建

细胞周期蛋白依赖性激酶(Cyclin-dependent Kinases, CDKs)是细胞周期调控的重要因子, 也是治疗癌症的一类重要的药物靶标. 靛玉红是传统中药当归龙荟丸中治疗慢性疾病的有效成分, 靛玉红及其衍生物5-磺酸基-靛玉红对CDKs具有有效的抑制作用. 以获得晶体结构的CDK2与5-磺酸根-靛玉红的复合物为模板, 通过同源模建和分子对接的方法构建出的CDK4与靛玉红及其衍生物的结合模式. 结合CDK4与两种抑制剂的复合物结构, 解释了靛玉红和衍生物5-磺酸基-靛玉红之间抑制活性的差别, 同时也分析了5-磺酸基-靛玉红对CDK2和CDK4不同选择性的原因. 所建CDK4结构为进一步进行基于结构的抗癌药物设计提供了合理的模型.     

应用MM/PBSA方法研究CDK2活性口袋内溶剂水分子对CDK2-配体结合自由能的影响

应用MM/PBSA方法研究了CDK2活性口袋内溶剂水分子对CDK2-配体结合自由能的影响. 结果表明, 活性口袋内溶剂水分子对CDK2-配体相互作用自由能有一定的贡献, 其贡献的大小随配体不同而有所差异, 导致这种差异的主要原因是活性位点内溶剂水分子与蛋白残基和配体之间形成了不同的氢键相互作用网络.     

3D-QSAR和分子对接研究吲哚咔唑类细胞周期蛋白激酶抑制剂的选择性

细胞周期蛋白激酶(cyclin-dependent kinases, CDKs)是近年来治疗肿瘤的重要靶标. 由于大多数激酶ATP结合位点的保守性, CDK选择性激酶抑制剂的开发成为当前的研发难点和热点. 针对吲哚咔唑类CDK抑制剂, 我们采用比较分子力场分析方法(CoMFA)建立了CDK2-QSAR(quantitative structure-activity relationship)和CDK4-QSSR(quantitative structure-selectivity relationship)模型. 所建模型的交叉验证系数q2分别为0.722和0.703; 非交叉验证系数r2分别为0.977和0.946, 表明其具有较好的预测能力. 同时, 用分子对接的方法分析了这类化合物与CDK4同源模建结构的作用模式, 根据这两个模型发现, 吲哚咔唑类化合物的R5和R6位长链取代对CDK4的选择性具有一定的影响, 而且结合其作用模式比较合理地解释了这类抑制剂的选择性原因, 这对CDKs的选择性研究具有一定的指导意义.     

靛玉红类CDK1抑制剂的同源模建、分子对接及3D-QSAR研究

细胞周期蛋白依赖性激酶1的异常表达会导致G2期的停滞及多种肿瘤的发生,故CDK1近年来已成为一个理想的治疗靶点.本文以细胞分裂调控蛋白2的同源体为模板,同源模建了CDK1的结构,并与靛玉红类小分子抑制剂进行分子对接.分别运用三种叠合方法进行分子叠合,并在此基础上采用Sybyl 7.1中的比较分子场分析(CoMFA)模块及Discovery Studio 3.0中的三维定量构效关系(3D-QSAR)模块(以下简称为DS)分别建立了3D-QSAR模型.其中,将分子对接叠合与公共骨架叠合联合运用的叠合方法所得3D-QSAR模型的评价参数是最佳的(CoMFA:q2=0.681,r2=0.909,r2pred.=0.836;DS:q2=0.579,r2=0.971,r2pred.=0.795,其中q2为交叉验证系数,r2为非交叉验证系数).本文的研究结果在对靛玉红类小分子进行结构修饰设计出新的CDK1抑制剂方面,可提供重要的理论基础.     

高通量虚拟筛选CDK2/Cyclin A2靶点抑制剂

CDK2/Cyclin A2复合蛋白的异常表达与乳腺癌、 口腔癌、 食管鳞状细胞癌的发生密切相关. CDK2/ Cyclin A2复合蛋白的活性位点不同于CDK2单体. 至今临床上尚无靶向此复合蛋白的药物分子. 针对CDK2/Cyclin A2复合蛋白, 以实验报道的10个抑制剂分子构建药效团模型, 通过药物体外药代动力学（ADME）、 Docking、 聚类分析、 毒性预测, 从DrugBank, ChEMBL和TCM@Taiwan 3个数据库约90万组数据中进行高通量虚拟筛选, 进一步进行MD模拟、 MM/PBSA结合自由能计算、 能量分解和平均非共价作用(aNCI)分析, 筛选出3个抑制效果优于阳性实验药Roscovitine的先导分子: DrugBank-2004, DrugBank-583和ChEMBL-7122. 与CDK2蛋白相比, CDK2/Cyclin A2复合蛋白结合位点空间变大, 先导分子与Lys33, Asp86, Lys129和Asp145残基之间的排斥作用有所降低, 导致结合自由能更大.     

Design, Synthesis and Preliminary Biological Evaluation of Purine-2,6-diamine Derivatives as Cyclin-dependent Kinase （CDK） Inhibitors

Novel purine-2,6-diamine derivatives were designed and synthesized as cyclin-dependent kinase （CDK） inhibi- tors. According to the preliminary biological evaluation, most of the compounds show good inhibitory activities in CDK1 enzyme assay and potent antiproliferative activities in some tumor cell lines. Especially, compound lla （IC50=0.35 μmol/L for CDK1/cyclin B and IC50： effect compared with Roscovitine （IC50= 2.54 CDK2/cyclin A）. 0.023 μmol/L for CDK2/cyclin A） possessed better inhibitory μmol/L for CDK1/cyclin B and IC50=0.092 μ mol/L for     

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.     

靛玉红类CDK1抑制剂的同源模建、分子对接及3D-QSAR研究

细胞周期蛋白依赖性激酶1的异常表达会导致G2期的停滞及多种肿瘤的发生,故CDK1近年来已成为一个理想的治疗靶点. 本文以细胞分裂调控蛋白2的同源体为模板,同源模建了CDK1的结构,并与靛玉红类小分子抑制剂进行分子对接. 分别运用三种叠合方法进行分子叠合,并在此基础上采用Sybyl 7.1中的比较分子场分析(CoMFA)模块及Discovery Studio 3.0中的三维定量构效关系(3D-QSAR)模块(以下简称为DS)分别建立了3D-QSAR模型. 其中,将分子对接叠合与公共骨架叠合联合运用的叠合方法所得3D-QSAR模型的评价参数是最佳的(CoMFA：q²=0.681,r²=0.909,r_pred.²=0.836; DS：q²=0.579,r²=0.971,r_pred.²=0.795,其中q²为交叉验证系数,r²为非交叉验证系数). 本文的研究结果在对靛玉红类小分子进行结构修饰设计出新的CDK1抑制剂方面,可提供重要的理论基础.     

基于机器学习方法预测CDK4的抑制剂

最近的研究已经证实,以周期蛋白依赖性激酶4(cyclin-dependent kinase 4,CDK4)为靶点,通过CDK4的抑制剂重新建立细胞周期的调控在肿瘤靶向治疗的发展中已经成为有吸引力的方向。本文测试了三种机器学习方法,k最近邻、C4.5决策树和随机森林(random forest,RF),用于预测CDK4的抑制剂。所建这些模型都达到了令人满意的预测效果。其中,RF模型当参数Mtry=13、jbt=255时对应的总预测精度最大,为96.65%。同时,与CDK4抑制剂最相关的25个分子描述符也被最优的RF模型挑选了出来。本文的研究表明,机器学习方法特别是RF方法,对于发现潜在的CDK4抑制剂十分有效。     

分子模拟方法研究四氢化吡啶并[1,2-a]吲哚酮衍生物对GSK3β和CDK5的选择性

本文通过分子对接,分子动力学模拟(MD)和MM/PBSA能量计算的方法,从分子水平研究了3个四氢化吡啶并[1,2-a]吲哚酮衍生物与CDK5和GSK3β的相互作用,并揭示了这些抑制剂对GSK3β的选择性抑制机理。分子对接结果表明,抑制剂对2种激酶具有相似的结合模式,结合口袋处的残基也都根据晶体结构的序列比对相互对应。研究体系的RMSD随时间的稳定变化,表明模拟体系已达到稳定状态,因而后续的分析是可靠的。CDK5/抑制剂体系,RMSD在0.15 nm上下波动,CDK5/M1和CDK5/M2骨架轻微波动,稍高于CDK5/M3;而GSK3β体系的RMSD值略高于CDK5体系,在0.17 nm上下波动,GSK3β/M1和GSK3ββ/M2的骨架波动平衡值则稍低于GSK3β/M3。活性较大的抑制剂增强了蛋白骨架整体的"柔性",即对激酶构象产生一定影响。能量分析表明,静电能和范德华作用能够区分不同抑制剂对同种激酶的生物活性差异。极性溶剂化自由能对区分抑制剂选择性也很重要,残基分解表明GSK3β的Glu97、Thr138是造成抑制剂选择性的主要原因。抑制剂与CDK5和GSK3β结合的过程中,蛋白质残基的动态相关性存在差异,铰链区域的Thr138与Val135~Gln206区域残基正相关,证实Thr138残基是区分抑制剂选择性的关键。     

Bound and scattering states for a hyperbolic‐type potential in view of a new developed approximation

A new developed approximation is used to obtain the arbitrary l‐wave bound and scattering state solutions of Schrödinger equation for a particle in a hyperbolic‐type potential. For bound state, the energy eigenvalue equation and unnormalized wave functions in terms of Jacobi polynomials are achieved using the Nikiforov–Uvarov (NU) method. Besides, energy eigenvalues are calculated numerically for some states and compared with those given in the literature to check accuracy of our results. For scattering state, the wave function is found in terms of hypergeometric functions. Furthermore, scattering amplitude and phase shifts are achieved using scattering solutions. Also it is shown that the energy eigenvalue equation obtained from analytic property of scattering amplitude is same with one obtained using NU method. © 2015 Wiley Periodicals, Inc.     

Application of neutron activation analysis in a fission molybdenum separation study

The separation of⁹⁹Mo from low-enriched uranium (LEU, 19.5%²³⁵U) targets was evaluated using natural uranium (NU) and non-radioactive tracers. Neutron activation analysis was used to determine (1) the efficiency of molybdenum recovery and (2) the decontamination factor of numerous fission product elements from the molybdenum product. Using NU and non-radioactive elements simplified procedures and allowed tests to be completed in a fume hood instead of a shielded cell. During activation of the non-radioactive tracers, uranium fission occurs, which can interfere with subsequent gamma-ray analysis. A comparison was made of the interferences caused by these fission products from both NU and LEU.     

Structure–Activity Relationship Study of a Potent α-Thrombin Binding Aptamer Incorporating Hexitol Nucleotides

The replacement of one or more nucleotide residues in the potent α-thrombin-binding aptamer NU172 with hexitol-based nucleotides has been devised to study the effect of these substitutions on the physicochemical and functional properties of the anticoagulant agent. The incorporation of single hexitol nucleotides at the T9 and G18 positions of NU172 substantially retained the physicochemical features of the parent oligonucleotide, as a result of the biomimetic properties of the hexitol backbone. Importantly, the NU172- T ^H9 mutant exhibited a higher binding affinity toward human α-thrombin than the native aptamer and an improved stability even after 24 h in 90 % human serum, with a significant increase in the estimated half-life. The anticoagulant activity of the modified oligonucleotide was also found to be slightly preferable to NU172. Overall, these results confirm the potential of hexitol nucleotides as biomimetic agents, while laying the foundations for the development of NU172-inspired α-thrombin-binding aptamers.     

Clinical count rate performance of an LSO PET/CT scanner utilizing a new front-end electronics architecture with sub-nanosecond intrinsic timing resolution

A new front-end electronics architecture with sub-nanosecond intrinsic timing resolution has recently been incorporated into a 16 slice LSO PET/CT scanner for imaging applications in oncology. The new electronics are designed to work optimally with the lutetium orthosilicate (LSO) scintillator. Clinical performance of the LSO PET/CT is examined before and after upgrading to the new PICO 3D electronics, and compared with results using the NEMA NU 2 standard for evaluating scanner performance. Improved noise-equivalent count rates are seen in clinical studies, and reduced scatter fractions are observed, consistent with the increased lower-level energy threshold used to reject scatter events in the upgraded configuration.     

The mechanism of the electrochemical reduction of 5-nitrouracil

The electrochemical reduction of 5-nitrouracil (5NU) has been investigated on Ag-Hg cathode in DMSO by cyclic voltammetry and controlled potential electrolysis, in combination with UV and ESR spectroscopies. The results showed that 5NU proceeds in a four-electron reduction and simultaneously participates in the reaction as a proton donor. At a more negative potential, the 5NU anion (5NU^?) thus formed is reduced further through a one-electron process to a dianion whose ESR parameters have been determined as a_N = 14.6 G, a_H = 5.2 G and g = 2.005. The radical decay process might be conjectured through protonization by accepting protons from 5NU, of which the rate constant k₁ = 52 M^?1·s^?1.     

Discovery of rare sulfated N-unsubstituted glucosamine based heparan sulfate analogs selectively activating chemokines

Achieving selective inhibition of chemokines with structurally well-defined heparan sulfate (HS) oligosaccharides can provide important insights into cancer cell migration and metastasis. However, HS is highly heterogeneous in chemical composition, which limits its therapeutic use. Here, we report the rational design and synthesis of N-unsubstituted (NU) and N-acetylated (NA) heparan sulfate tetrasaccharides that selectively inhibit structurally homologous chemokines. HS analogs were produced by divergent synthesis, where fully protected HS tetrasaccharide precursor was subjected to selective deprotection and regioselectively O-sulfated, and O-phosphorylated to obtain 13 novel HS tetrasaccharides. HS microarray and SPR analysis with a wide range of chemokines revealed the structural significance of sulfation patterns and NU domain in chemokine activities for the first time. Particularly, HT-3,6S-NH revealed selective recognition by CCL2 chemokine. Further systematic interrogation of the role of HT-3,6S-NH in cancer demonstrated an effective blockade of CCL2 and its receptor CCR2 interactions, thereby impairing cancer cell proliferation, migration and invasion, a step towards designing novel drug molecules.     

Metal–Organic Frameworks for Oxygen Storage

We present a systematic study of metal–organic frameworks (MOFs) for the storage of oxygen. The study starts with grand canonical Monte Carlo simulations on a suite of 10 000 MOFs for the adsorption of oxygen. From these data, the MOFs were down selected to the prime candidates of HKUST‐1 (Cu‐BTC) and NU‐125, both with coordinatively unsaturated Cu sites. Oxygen isotherms up to 30 bar were measured at multiple temperatures to determine the isosteric heat of adsorption for oxygen on each MOF by fitting to a Toth isotherm model. High pressure (up to 140 bar) oxygen isotherms were measured for HKUST‐1 and NU‐125 to determine the working capacity of each MOF. Compared to the zeolite NaX and Norit activated carbon, NU‐125 has an increased excess capacity for oxygen of 237 % and 98 %, respectively. These materials could ultimately prove useful for oxygen storage in medical, military, and aerospace applications.     

Interaction energies for the purine inhibitor roscovitine with cyclin-dependent kinase 2: correlated ab initio quantum-chemical, DFT and empirical calculations

The interaction between roscovitine and cyclin-dependent kinase 2 (cdk2) was investigated by performing correlated ab initio quantum-chemical calculations. The whole protein was fragmented into smaller systems consisting of one or a few amino acids, and the interaction energies of these fragments with roscovitine were determined by using the MP2 method with the extended aug-cc-pVDZ basis set. For selected complexes, the complete basis set limit MP2 interaction energies, as well as the coupled-cluster corrections with inclusion of single, double and noninteractive triples contributions [CCSD(T)], were also evaluated. The energies of interaction between roscovitine and small fragments and between roscovitine and substantial sections of protein (722 atoms) were also computed by using density-functional tight-binding methods covering dispersion energy (DFTB-D) and the Cornell empirical potential. Total stabilisation energy originates predominantly from dispersion energy and methods that do not account for the dispersion energy cannot, therefore, be recommended for the study of protein-inhibitor interactions. The Cornell empirical potential describes reasonably well the interaction between roscovitine and protein; therefore, this method can be applied in future thermodynamic calculations. A limited number of amino acid residues contribute significantly to the binding of roscovitine and cdk2, whereas a rather large number of amino acids make a negligible contribution.     

Urea nitrate and nitrourea: powerful and regioselective aromatic nitration agents

Urea nitrate (UN) and nitrourea (NU), easily prepared from urea and nitric acid, convert deactivated aromatic compounds to the corresponding nitrated derivatives with a high yield and a high regioselectivity under very mild conditions. The performance of the two reagents is quite similar indicating that NU is an intermediate in the UN nitration process.     

Comment on “a new approach to solve the Schrödinger equation with an anharmonic sextic potential”

We analyze a recent application of the Nikiforov-Uvarov (NU) method to an N -dimensional anharmonic oscillator with a central-field sextic potential-energy function. We show that most of the equations derived by the author exhibit errors (or typos) and that his interpretation of the results may not be correct. By means of the Frobenius (power-series) method we derive exact particular solutions to the Schrödinger equation and compare them with those coming from the NU method.