Pharmacophore modeling, 3D-QSAR studies, and in-silico ADME prediction of pyrrolidine derivatives as neuraminidase inhibitors

Neuraminidase (NA) is a major glycoprotein of influenza virus which is essential for viral infection. It offers a potential target for antiviral drug development. To develop potent NA inhibitors, pharmacophore models were generated by genetic algorithm with linear assignment for hypermolecular alignment of data sets. 3D-QSAR studies were carried out on 49 molecules. Both comparative molecular field analysis (q(2) = 0.720 and r(2) = 0.947) and comparative molecular similarity indices analysis (q(2) = 0.644 and r(2) = 0.885) yielded reasonable results. A preliminary pharmacokinetic profile of these neuraminidase inhibitors was predicted using Volsurf module.     

探讨BV三项在阴道分泌物检测中的临床价值

目的：探讨细菌性阴道病（Backrial Vagimsis,BV）三项实验在阴道分泌物检测中诊断细菌性阴道病的临床价值。方法：对门诊210例来诊妇产科患者做过氧化氢酶、唾液酸苷酶、白细胞脂酶三项实验和显微镜检查。结果：BV的患病率为41．4％,滴虫性阴道炎4.3％,霉菌性阴道炎23.8％,BV的患病率明显高于其他的阴道炎。结论：门诊就医的妇产科患者BV的患病率很高,应该把BV三项作为妇产科常规的筛选实验。     

基于神经氨酸酶活性检测的板蓝根品质的生物评价

采用流感病毒神经氨酸酶 (NA) 体外活性荧光检测法测定板蓝根的NA抑制生物活性, 并建立板蓝根抗病毒生物效价检测方法。研究表明板蓝根具有抑制NA的活性, IC₅₀ = (0.90 ± 0.20) mg·mL^-1 (相当于生药), 其量效曲线形状与阳性对照药磷酸奥司他韦相似, 提示二者对NA的抑制可能具有相同的作用方式。采用“质反应平行线”法设计和优化的板蓝根抗病毒生物效价检测方法, 重复性较好 (RSD = 5.78%), 实际样品检测结果均能通过可靠检验 (偏离直线P > 0.05、偏离平行P > 0.05)。研究结果表明, 所建立的生物效价检测方法可以作为板蓝根品质生物评价的方法之一。     

On Three‐Dimensional Holographic Vector of Atomic Interaction Field Analysis for Influenza Neuraminidase Inhibitors

Influenza is a major respiratory infection associated with significant morbidity in the general population and mortality in elderly and high‐risk patients. It is an RNA virus that contains two major surface glycoproteins, neuraminidase and hemagglutinin. These proteins are essential for infection. Neuraminidase has been found to be a potential target to control influenza virus. Here, we have developed three‐dimensional holographic vector of atomic interaction field analysis as a new method of quantitative structure–activity relationships for different sets of compounds to understand chemical–biological interactions governing their activities toward influenza neuraminidase. Good results, R = 0.885, SD = 0.848, R_CV = 0.858 (the maximum) and SD_CV = 0.934 (the minimum), showed that holographic vector of atomic interaction field analysis can be applicable to molecular structural characterization and biological activity prediction and quantitative structure–activity relationship model had favorable stability and prediction capability.     

Total ganglioside ablation at mouse motor nerve terminals alters neurotransmitter release level

Neuronal membrane gangliosides, forming a large family of sialylated glycosphingolipids, have been hypothesized to play important roles in synaptic transmission. We studied the ex vivo electrophysiological function of neuromuscular junctions of GM2/GD2‐synthase*GD3‐synthase compound null‐mutant mice after acute removal of GM3, the only remaining ganglioside in this mouse, by in vitro treatment with neuraminidase. We found 16% enhancement of the acetylcholine release per nerve impulse at low‐rate (0.3 Hz) nerve stimulation. Conversely, the treatment reduced the acetylcholine release evoked by high‐rate (40 Hz) nerve stimulation. Also, 25 ms paired‐pulse facilitation of endplate potentials was reduced by the neuraminidase‐treatment. These effects may indicate a modest modulatory influence of the negative electrical charges carried by the sialic acid molecules of gangliosides on the function of presynaptic Ca_v2.1 channels, affecting the magnitude and kinetics of the Ca²⁺ influx that induces neurotransmitter release from the motor nerve terminal. Our results show that gangliosides are to some extent involved in neurotransmission at the neuromuscular junction, but that their presence is not an absolute requirement in this process. Synapse 64:335–338, 2010. © 2009 Wiley‐Liss, Inc.     

羧肽酶B消除C4副带后对湖北地区C4基因频率及家系C4单体型与补体型的检测

人的补体第四成份(C4)具有高度多态性,其别型的经典检测法仅用神经氨酸酶预处理血浆,这样电泳后每一C4别型表现3条区带,一主两副,定型困难。最新发现,加用羧肽酶B预处理血浆,可以消除副带,使定型变易,且更准确。我们用新的方法重新对湖北地区汉族人的C4基因频率、C4单体型与补体型进行了测定,发现两法结果基本类似,略有区别。鉴于新法优越,建议今后作为检测C4多态性的常规方法。     

Management of influenza symptoms in healthy adults

OBJECTIVE: To determine the cost-effectiveness of rapid diagnostic testing and empiric antiviral therapy for healthy adults with symptoms of influenza. DESIGN: Cost-effectiveness analysis using a decision model based on previously published data. Outcome measures included costs and quality-adjusted life expectancy. SETTING: Physician's office. PATIENTS/PARTICIPANTS: Hypothetically healthy, working adults < 65 years of age presenting with cough and fever during the influenza season. INTERVENTIONS: Rapid testing or clinical diagnosis followed by treatment with amantadine, rimantadine, oseltamivir, or zanamivir compared with no antiviral therapy. RESULTS: Base-case analysis: not giving antiviral therapy is the most expensive and least effective strategy, costing 471 dollars per patient, mostly owing to time lost from work. Amantadine treatment increases life expectancy by 0.0014 quality-adjusted life years (QALYs) while saving 108 dollars per patient relative to no antiviral therapy. Zanamivir is slightly more effective than amantadine, adding 0.0002 QALYs at an incremental cost of 31 dollars, or 133,000 dollars per QALY saved. All other strategies, including testing strategies, are both less effective and more expensive. SENSITIVITY ANALYSIS: The model is sensitive to the probability of influenza infection, proportion of influenza caused by type B, the relative efficacy of the various drugs, and the value of a workday. At a clinical probability of influenza infection > 20%, antiviral therapy is favored. As the proportion of influenza B increases, zanamivir is favored over amantadine. Testing is rarely indicated. Ignoring the costs of lost workdays, amantadine treatment costs 1,200 dollars/QALY saved. CONCLUSIONS: Antiviral therapy with either amantadine or zanamivir is cost-effective for healthy, young patients with influenza-like illness during the influenza season, depending on the prevalence of influenza B.     

传统中药中H7N9病毒神经氨酸酶抑制剂的计算机虚拟筛选

目的:运用计算机虚拟筛选技术从传统中药数据库(TCM database@Taiwan)中快速搜索H7N9亚型流感病毒神经氨酸酶(neuraminidase,NA)的中药小分子抑制剂。方法:采用Auto Dock Vina软件对蛋白质晶体结构数据库PDB中NA与小分子抑制剂扎那米韦形成的复合物(PDB代码为4MWX)三维结构活性部位进行分析,基于传统中药配体库进行分子对接初次筛选。综合运用传统中药系统药理学数据库及分析平台TCMSP及Accelrys公司开发的Discovery Studio 2.5分子模拟软件包内TOPKAT模块计算药代动力学参数和毒性预测对分子对接结果进行2次筛选。结果:以原配体(扎那米韦)的自由结合能为阈值,筛选出中国传统中药数据库中3个类药性良好的化学成分与NA亲和力高于上市的抗流感药物扎那米韦的天然小分子化合物,并且确定了它们的中草药来源。结论:该研究结果可促进从传统中药库中提取、设计及实验合成新抗H7N9流感病毒药物。