重症肌无力免疫吸附剂的制备及性能研究

重症肌无力患者体内致病毒素是乙酰胆碱的受体抗体.通过对载体材料的优化及对配基的筛选发现,使用质量分数为6%的纤维素球形载体,以环氧氯丙烷法活化并固定上L-色氨酸作为配基制备的血液灌流材料在静态吸附实验(1g吸附剂加入3mL病人血清,室温,3h)中可使抗体水平下降25%以上,吸附量达3.669×10^-3nmol/g,选择性较高,具有应用前景.     

激酶抑制剂的计算机辅助设计

激酶是当今的第二大靶标,其高选择性、强活性抑制剂的开发是医药化学的前沿领域。本文介绍了生物信息学——多序列比对、QSAR、药效团方法、同源模建、高通量虚拟筛选、分子动力学与自由能计算、QM-MM和计算系统生物学等计算机辅助设计方法在激酶抑制剂设计中的重要应用。     

极光激酶A抗癌抑制剂的高通量筛选及对接研究

极光激酶(aurora kinases)A是负责调控细胞有丝分裂的一类重要的丝氨酸/苏氨酸激酶. 用极光激酶A的一种抑制剂H-89作为先导化合物, 通过AutoDock vina软件进行虚拟筛选, 选取能量打分最低的抑制剂(命名为H-89-1)做进一步的深入研究. 理论对接研究揭示H-89-1是一种比H-89更好的抑制剂, 并且Thr217和Arg137是H-89-1和酶作用中的重要残基, 因为它们和H-89-1形成了氢键. 我们的研究将为极光激酶A专有抑制剂的设计提供可靠的理论线索.     

GSH特异的人单链抗体计算机辅助结构研究

以还原型谷胱甘肽 (GSH)的两种衍物作为半抗原 ,从半人工合成的人单链抗体库中筛选得到了多株特异结合的单链抗体 .从中选择亲合力最强的单链抗体进行了基因的重组和测序 .根据由核苷酸测定结果而推导的氨基酸残基序列 ,用计算机模拟分析了两株单链抗体的空间结构 .结果显示单链抗体以二聚体形式存在 ,与单链抗体蛋白SDS_PAGE电泳结果相一致 .抗原结合部位———重链CDR3区位抗体的表面 ,且形成一个凹腔 ,因此可推测位于CDR3区的丝氨酸最可能参与硒化反应     

Screening and Mechanism of Novel Angiotensin-I-Converting Enzyme Inhibitory Peptides in X. sorbifolia Seed Meal: A Computer-Assisted Experimental Study Method

Angiotensin-I-converting enzyme (ACE) inhibitors are used extensively to control hypertension. In this study, a computer-assisted experimental approach was used to screen ACE-inhibiting peptides from X. sorbifolum seed meal (XSM). The process conditions for XSM hydrolysis were optimized through the orthogonal experimental method combined with a database. The optimal conditions for ACE inhibition included an alkaline protease dose of 5%, 45 °C, 15 min and pH 9.5. The hydrolysate was analyzed by LC-MS/MS, and 10 optimal peptides were screened. Molecular docking results revealed four peptides (GGLPGFDPA, IMAVLAIVL, ETYFIVR, and INPILLPK) with ACE inhibitory potential. At 0.1 mg/mL, the synthetic peptides GGLPGFDPA, ETYFIVR, and INPILLPK provided ACE inhibition rates of 24.89%, 67.02%, and 4.19%, respectively. GGLPGFDPA and ETYFIVR maintained high inhibitory activities during in vitro digestions. Therefore, the XSM protein may be a suitable material for preparing ACE inhibitory peptides, and computer-assisted experimental screening is an effective, accurate and promising method for discovering new active peptides.     

计算机辅助三聚氰胺分子印迹聚合物的制备

以三聚氰胺(MAM)为印迹分子,丙烯酰胺(AM)、甲基丙烯酸(MAA)、N,N-亚甲基双丙烯酰胺(MBA)和衣康酸(IA)为功能单体,二乙烯基苯(DVB)、乙二醇双甲基丙烯酸酯(EGDMA)和三羟甲基丙烷三甲基丙烯酸酯(TRIM)为交联剂,采用量子化学密度泛函理论的长程校正方法模拟并探讨了MAM与4种功能单体的成键作用位点、成键数目、印迹反应摩尔比及印迹作用机理.依据结合能(ΔE)优化了功能单体和交联剂,并借助分子中原子理论(AIM)揭示了MAM与功能单体印迹作用的本质.计算结果表明,MAM通过氢键与4种功能单体以摩尔比1∶6进行印迹聚合,其中IA与MAM形成的复合物结合能最低,结构最稳定;与TRIM和EGDMA交联剂相比,DVB与MAM结合能最低,更适合作为MAM-IA印迹聚合物的交联剂.采用沉淀聚合法合成MAM分子印迹聚合物(MAM-MIPs)并测定其吸附性,当MAM与IA印迹摩尔反应比为1∶6时,以DVB为交联剂时制备的MAM-MIPs吸附性最好,其微球平均粒径为195 nm;Scatchard分析结果表明,在所研究的浓度范围内MIPs对印迹分子MAM的结合位点是等价的,其最大表观吸附量Qmax为20.79mg/g,离解平衡常数Kd为58.82 mg/L;与环丙氨嗪(CYR)、三聚氰酸(CYA)和三聚硫氰酸(TRI)在牛奶中的吸附量相比,MAM-MIPs对MAM表现出较强的特异吸附能力.     

Exponential repulsion improves structural predictability of molecular docking

Molecular docking is a powerful tool for theoretical prediction of the preferred conformation and orientation of small molecules within protein active sites. The obtained poses can be used for estimation of binding energies, which indicate the inhibition effect of designed inhibitors, and therefore might be used for in silico drug design. However, the evaluation of ligand binding affinity critically depends on successful prediction of the native binding mode. Contemporary docking methods are often based on scoring functions derived from molecular mechanical potentials. In such potentials, nonbonded interactions are typically represented by electrostatic interactions between atom‐centered partial charges and standard 6–12 Lennard–Jones potential. Here, we present implementation and testing of a scoring function based on more physically justified exponential repulsion instead of the standard Lennard–Jones potential. We found that this scoring function significantly improved prediction of the native binding modes in proteins bearing narrow active sites such as serine proteases and kinases. © 2016 Wiley Periodicals, Inc.     

陶工尘肺辅助性诊断的方法研究——测定发中微量元素 建立判别方程

测定了陶工Ｉ期尘肺患者的头发中Ｚｎ、Ｃｕ、Ｓｅ、Ｎｉ、Ｆｅ、Ｍｎ、Ｍｇ７种金属元素，用陶工可疑患者作对照，建立Ｆｉｓｈｅｒ判别方程，对陶工尘肺进行判别。自身回代正确率９４．４４％，前瞻性回代达８３．３３％，各其流行病学指标计算均属良好。     

计算机模式识别法在类风湿中医证侯的研究

根据计算机模式识别的马氏(Mahalanobis)距离判别法，用BASIC等语言缩制的IBM-PC等徽机适用的多元统计判别程序将健康人分别与类风湿性关节炎的寒热错杂型、寒湿阻络型及肝肾两虚型的发样徽量元素Zn、Fe、Cu、Cd及Zn／Cu五种因素进行分类判别．结果表明以Zn、Ft、Zn／Cu为特征参量．健康人与寒热情杂型类风温性关节炎患者分类准确亭为95．6%，而分别以Zn、Cu和Zn，Fe、Cu为特征参量．健康人与寒湿阻络型和肝肾两虚型患者分类准确率分别为100％和90．2％．说明以Fe、Cu、Zn(或Zn／Cu)组成的微量元素谱含量，在不同中医证型的类风温性关节炎和健康中是有差异的。     

Theoretical Exploring of a Molecular Mechanism for Melanin Inhibitory Activity of Calycosin in Zebrafish

Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin in the human body. Overproduction of melanin can lead to a variety of skin disorders. Calycosin is an isoflavone from Astragali Radix, which is a traditional Chinese medicine that exhibits several pharmacological activities including skin whitening. In our study, the inhibitory effect of calycosin on melanin production is confirmed in a zebrafish in vivo model by comparing with hydroquinone, kojic acid, and arbutin, known as tyrosinase inhibitors. Moreover, the inhibitory kinetics of calycosin on tyrosinase and their binding mechanisms are determined using molecular docking techniques, molecular dynamic simulations, and free energy analysis. The results indicate that calycosin has an obvious inhibitory effect on zebrafish pigmentation at the concentration of 7.5 μM, 15 μM, and 30 μM. The IC₅₀ of calycosin is 30.35 μM, which is lower than hydroquinone (37.35 μM), kojic acid (6.51 × 10³ μM), and arbutin (3.67 × 10⁴ μM). Furthermore, all the results of molecular docking, molecular dynamics simulations, and free energy analysis suggest that calycosin can directly bind to the active site of tyrosinase with very good binding affinity. The study indicates that the combination of computer molecular modeling and zebrafish in vivo assay would be feasible in confirming the result of the in vitro test and illustrating the target-binding information.     

Structural Bases for Hesperetin Derivatives: Inhibition of Protein Tyrosine Phosphatase 1B,Kinetics Mechanism and Molecular Docking Study

In the present study, we investigated the structure-activity relationship of naturally occurring hesperetin derivatives, as well as the effects of their glycosylation on the inhibition of diabetes-related enzyme systems, protein tyrosine phosphatase 1B (PTP1B) and α-glycosidase. Among the tested hesperetin derivatives, hesperetin 5-O-glucoside, a single-glucose-containing flavanone glycoside, significantly inhibited PTP1B with an IC₅₀ value of 37.14 ± 0.07 µM. Hesperetin, which lacks a sugar molecule, was the weakest inhibitor compared to the reference compound, ursolic acid (IC₅₀ = 9.65 ± 0.01 µM). The most active flavanone hesperetin 5-O-glucoside suggested that the position of a sugar moiety at the C-5-position influences the PTP1B inhibition. It was observed that the ability to inhibit PTP1B is dependent on the nature, position, and number of sugar moieties in the flavonoid structure, as well as conjugation. In the kinetic study of PTP1B enzyme inhibition, hesperetin 5-O-glucoside led to mixed-type inhibition. Molecular docking studies revealed that hesperetin 5-O-glucoside had a higher binding affinity with key amino residues, suggesting that this molecule best fits the PTP1B allosteric site cavity. The data reported here support hesperetin 5-O-glucoside as a hit for the design of more potent and selective inhibitors against PTP1B in the search for a new anti-diabetic treatment.     

AT1受体的中药活性成分筛选模型及其作用机理研究

传统中药对治疗心血管类疾病疗效显著,例如钩藤、黄芪、益母草等在临床应用广泛.现代药理研究表明钩藤碱可以降压;黄芪中毛蕊异黄酮能舒张血管平滑肌、保护心脑血管;益母草碱可扩张微血管,改善血液流变异常,但它们分子层面作用机制尚不明确.首先以牛视紫红质蛋白为模板,模建出心血管疾病主要靶点AT1受体的三维结构.然后将AT1受体拮抗剂和中药活性成分与受体模型结合的作用方式进行了对比研究,据此提出了中药活性成分治疗心血管疾病的作用机理,并建立了AT1受体的中药活性成分筛选模型.结果表明:黄芪毛蕊异黄酮等中药活性成分能与AT1受体活性口袋中的残基发生氢键作用,结合方式与AT1受体拮抗剂相似.每一种AT1受体拮抗剂均与His183,Lys199,His256,Gln257,Ser105,Ser109,Tyr113,Asn200中多个发生氢键作用;黄芪毛蕊异黄酮与Try113,Lys199,Gln257,Ser105发生氢键作用.本研究从分子层面上阐释了一些中药活性小分子的治病机理,为进一步挖掘中药资源,研究AT1受体相关的心脑血管类药物,合理设计和筛选AT1受体的拮抗剂提供重要依据.     

CAPA--Computer Aided Pesticide Analysis. Computer program for the automated evaluation of chromatographic data for residue analysis of foods

Pesticide residue analysis in food by means of gas chromatography with columns of different polarity and several selective detectors provides the analyst with a great number of chromatographic data. The introduction of personal computer based chromatographic data systems into research laboratories increased the efficiency of information management and organization; user designed software packages now have direct access to the stored data. The computer program CAPA (Computer Aided Pesticide Analysis) was developed for the interpretation and evaluation of chromatographic results. The program is written in TURBO PASCAL 3.0 and consists of several subprograms. In the main database all pesticides are filed in a multidimensional structure. The various subprograms have access to this catalog of retention and response data. Using the subprogram INTERPRET, which is the core of CAPA, the analyst is provided with all information necessary to interpret a gas chromatogram: identification of calibrated pesticides and estimation of their concentration. Automated screening analyses can be evaluated with the subprogram AUTOINTERPRET, an automated of INTERPRET that uses all relevant information stored in the data base. A report is produced containing the pesticides found in the sample and proposals how to confirm them best with the equipment and methods available. Finally the analyst has to make the decision about the probable presence and quantity of the indicated pesticides and to project the next confirmatory step by using INTERPRET.     

气相色谱法辅助分析环状1,3-二羰基化合物的去对称对映选择性还原反应机理

建立了一种利用气相色谱(GC)检测1,3-环戊二酮化合物去对称对映选择性还原反应转化率和产物含量的方法,作为一种重要辅助手段,用于磷中心手性膦酰胺催化环状1,3-二酮类化合物的去对称对映选择性还原反应机理的研究.样品经DB-WAX色谱柱(30 m×0.25 mm,0.25μm)分离,以标准化合物比对的方法,采用GC进行定性及定量分析,可简便、快速、准确测定在不同反应时间剩余原料和生成的不同产物的量.采用本方法对无添加剂和催化剂、只加入添加剂、只加入催化剂以及同时加入添加剂和催化剂4种情况下的反应进程进行了检测.结果表明,相比其它3种反应体系,同时加入添加剂N,N-二异丙基乙胺(DIPEA)和催化剂的反应体系的原料转化速度快,在5 min内反应转化率达到80％以上,单还原目标产物的含量接近70％.对照实验结果表明,加入DIPEA可大幅提高产物的对映选择性.本研究结果有助于深入理解相关反应的机理,即胺类添加剂的加入可促进手性活性催化物种的生成.     

A Theoretical Study of the Mechanism for the Photodecomposition of AgN3

IntroductionOrganic and inorganic azides have been an extensive investigated subject for manyyears['J. Azide compounds as the energetic materials have also been studied and character-ized[2], however, the kinetic characters have unsufficiently been studied in theory and experi-ment. In the 1930's it was discovered that the slow thermal decomposition of NaN3, KN3,AgNs and Pb(N,)2 was accompanied by very feeb1e 1uminescence, Which has been claimed tobe independent of the cations[3J, and coul…     

计算机辅助设计新型人脂肪酸合酶抑制剂及其抗肿瘤活性

以Orlistat为先导化合物,利用AutoDock进行计算机模拟对接,在对接结果中选择能量较低的6个结构进行合成与抗肿瘤活性筛选。以orlistat为原料,经2步反应制得苄基(2S,3S,5S)-2-己基-3,5-二羟基十六酸酯(2); 再经4步反应获得(3S,4S)-3-己基-4-［(S)-2-羟基十三烷基］氧杂环丁烷-2-酮(5); 5在EDCI作用下与酸经缩合反应合成了4个计新型人脂肪酸合酶抑制剂（6a~6d）,其中6b~6d为新化合物,其结构经¹H NMR, ¹³C NMR 和HR-MS（ESI）表征。体外初步活性测试表明：(S)-1-［(1S,2S)-3-己基-4-氧代氧杂环丁烷-2-基］十三烷-2-烟酸酯（6a）对MDA-MB-231细胞有较好的抑制作用,其IC₅₀为11.72 μmol·mL^-1,优于Orlistat(21.5 μmol·mL^-1)。     

The Therapeutic Effect and the Potential Mechanism of Flavonoids and Phenolics of Moringa oleifera Lam. Leaves against Hyperuricemia Mice

The aim of this study is to evaluate the anti-hyperuricemia effect and clarify the possible mechanisms of flavonoids and phenolics of MOL (MOL-FP) in mice. Hyperuricemia mice were generated via intraperitoneal (i.p.) administration of potassium oxonate (PO) and oral gavage (p.o.) of hypoxanthine (HX). Serum uric acid (UA), weight, serum XO activity, hepatic XO activity, urea nitrogen (BUN), creatinine (CRE), serum AST level, serum ALT level, mRNA expression of renal urate-anion transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporters 1 (OAT1), organic anion transporters 3 (OAT3), and ATP-binding cassette transporter G2 (ABCG2) were determined. The molecular docking was conducted using AutoDock Vina 1.2.0 to screen potential XO inhibitors in MOL-FP. Serum metabolomics was established to collect the metabolic profiles of mice and explore the metabolic changes that occurred after MOL-FP treatment. MOL-FP could notably reduce the serum UA level of hyperuricemia mice by inhibiting XO activity and regulating renal urate transporters. Molecular docking studies indicated that 5-p-coumaroylquinic acid, 3-p-coumaroylquinic acid, and catechin could be potential XO inhibitors. Besides, MOL-FP prevented the pathological process of hyperuricemia by regulating biomarkers associated with purine metabolism, amino acid metabolism, and lipid metabolism.     

两相滴定法研究溶剂萃取机理的通用计算机程序

基于Marquardt-Fletcher改进的Gauss-Newton法,编写了1个从pH滴定结果计算酸性萃取剂在两相溶液中的分配常数、在水溶液中的电离常数及其金属络合物在水相和有机相中形成常数的通用计算机程序SCTPT。本程序能计算含有20个M_iA_iH_k型络合物存在的两相体系,对初值无严格要求,可在4～15个数量级内变化,并已用于PMBP--Cu²⁺,PMBPZn²⁺的苯-水体系,结果满意。     

木犀草素抑制酪氨酸酶活性的分子机制

通过酶抑制动力学实验、荧光猝灭实验以及分子对接技术研究了木犀草素对酪氨酸酶活性的抑制作用。酶抑制动力学实验结果表明:木犀草素是酪氨酸酶的非竞争性抑制剂,抑制常数KI与IC50分别为86mmol/L和778.2μmol/L;荧光猝灭实验结果表明:木犀草素对酪氨酸酶产生静态荧光猝灭作用,疏水作用与氢键作用共同稳定其复合物结构,结合位点数为1;分子对接结果表明:木犀草素在酪氨酸酶疏水口袋边缘与其相互作用,相互作用力包括疏水作用力与氢键。     

Inhibition of Aldose Reductase by Ginsenoside Derivatives via a Specific Structure Activity Relationship with Kinetics Mechanism and Molecular Docking Study

This present work is designed to evaluate the anti-diabetic potential of 22 ginsenosides via the inhibition against rat lens aldose reductase (RLAR), and human recombinant aldose reductase (HRAR), using _DL-glyceraldehyde as a substrate. Among the ginsenosides tested, ginsenoside Rh2, (20S) ginsenoside Rg3, (20R) ginsenoside Rg3, and ginsenoside Rh1 inhibited RLAR significantly, with IC₅₀ values of 0.67, 1.25, 4.28, and 7.28 µM, respectively. Moreover, protopanaxadiol, protopanaxatriol, compound K, and ginsenoside Rh1 were potent inhibitors of HRAR, with IC₅₀ values of 0.36, 1.43, 2.23, and 4.66 µM, respectively. The relationship of structure–activity exposed that the existence of hydroxyl groups, linkages, and their stereo-structure, as well as the sugar moieties of the ginsenoside skeleton, represented a significant role in the inhibition of HRAR and RLAR. Additional, various modes of ginsenoside inhibition and molecular docking simulation indicated negative binding energies. It was also indicated that it has a strong capacity and high affinity to bind the active sites of enzymes. Further, active ginsenosides suppressed sorbitol accumulation in rat lenses under high-glucose conditions, demonstrating their potential to prevent sorbitol accumulation ex vivo. The findings of the present study suggest the potential of ginsenoside derivatives for use in the development of therapeutic or preventive agents for diabetic complications.