Exploring of drug leads from diversity-oriented Michael-acceptor library derived from natural products

A potential strategy for drug lead identification and in-active natural products re-discovery is elaborated.Starting from fifteen structurally diverse natural products,a focused library featured by Michael acceptors is constructed with IBX mediated oxidation.Biological assay on five tumor cell lines indicates that four Michael acceptors,8a,11a,12a,14a,are with improved cytotoxicity(3-10 folds more potent than the parent compounds),which merit further investigations.Further thiol-sensitive assay of the active hit 8a revealed that it was an irreversible Michael acceptor.The results suggest that the strategy is not only effective and relatively high discovery rate(28%),but also resource saving.

Multi-targeting cytotoxic drug leads from mushrooms

Due to genetic and epigenetic mechanisms, cancer have become a resistant disease and there is a need for new molecules having multiple targeting action that promotes apoptosis. Phytomolecules having multiple targeting anticancer activity are in high demand and there is less documentation or information available on these metabolites. It is evident that mushrooms are became the store houses of new anticancer molecules and mushrooms like Agaricus blazei, Antrodia camphorate, Albatrellus confluens, Bolteus badius, Cordyceps militaris, Clitocybe maxima, Funalia trogii, Grifola frondosa, and Inocybe umbrinella, are some of the medicinal mushrooms reported for their cytotoxic activity. Cytotoxic molecules like lentinan, grifolin, illudin-S, psilocybin, ganoderic acid, theanine, and hispolon, have been isolated from various mushroom species. However, studies have been limited only to in vitro cytotoxic mechanisms and very few trials have been conducted to prove the clinical efficacy of these drug leads. Hence, the current review focuses on new anticancer metabolites isolated from various mushrooms having multiple targeting mechanisms in cancer. However, an extensive research is needed to define the biosynthesis and clinical mechanism of these multiple acting metabolites. This review provides a platform for researchers new anticancer drugs and to bring out potent multiple acting anticancer newer drugs.

<i>In Silico</i>Pharmacological Analysis of a Potent Anti-Hepatoma Compound of Mushroom Origin and Emerging Role as an Adjuvant Drug Lead

Mushrooms are well-known to possess a continuum of anticancer metabolites that are vital in the development of anticancer adjuvant drug leads based on natural products. Owing to the fact that conventional cancer therapeutic methods were failed to lessen mortality caused by cancer to the estimated level with occurrence of adverse side effects, anticancer agents isolated from natural mushroom sources unarguably make an experimental research area worth mass focus today. The current study was targeted on in vitro cytotoxicity and in silico predictive pharmacological analysis of a flavonoid compound isolated from Fulvifomes fastuosus mushroom. Targeted compound was isolated from the mushroom using different chromatographic methods and identified by NMR spectrometry and mass spectrometry. Cytotoxicity experiments were carried out using MTT assay and apoptotic cells were identified by ethidium bromide/acridine orange staining. The SwissADME tool, BOILED-Egg construction model and Swiss target protein prediction software have been used to perform in silico predictive pharmacological analysis. The isolated compound has been identified as 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo[3,2-c]pyran-3,2'-furan]-3',4-dione by spectrometric methods. The result of MTT assay showed that 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo[3,2-c]pyran-3,2'-furan]-3',4-dione has potent anticancer activity for hepatoma against Hep-G2 cell line (IC50 = 20.8 μg/ml) being less toxic to normal CC-1 epithelial cells (IC50 = 167.00 μM). The cells treated with compound ex-hibited apoptotic features such as cellular shrinkage, nuclear fragmentation and condensed cytoplasm. In summary, 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo[3,2-c]pyran-3,2'-furan]-3',4-dione has shown potent anticancer properties against hepatoma with less cytotoxicity effect on normal cells. Furthermore, in silico study has revealed that properties of 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo[3,2-c]pyran-3,2'-furan]-3',4-dione may contribute to making a high absorption and clearance of the test compound as not interfering with the therapeutic failure of the compound. The properties of 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo-[3,2-c]pyran-3,2'-furan]-3',4-dione were compatible with well-known anticancer drug lapatinib. In conclusion, 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo[3,2-c]pyran-3,2'-furan]-3',4-dione has a high tendency to act as a good anticancer adjuvant drug in the treatment of hepatoma.

Precise assembly of inside-out cell membrane camouflaged nanoparticles via bioorthogonal reactions for improving drug leads capturing

Cell membrane camouflaged nanoparticles have been widely used in the field of drug leads discovery attribute to their unique biointerface targeting function.However,random orientation of cell membrane coating does not guarantee effective and appropriate binding of drugs to specific sites,especially when applied to intracellular regions of transmembrane proteins.Bioorthogonal reactions have been rapidly developed as a specific and reliable method for cell membrane functionalization without disturbing living biosystem.Herein,inside-out cell membrane camouflaged magnetic nanoparticles(IOCMMNPs)were accurately constructed via bioorthogonal reactions to screen small molecule inhibitors targeting intracellular tyrosine kinase domain of vascular endothelial growth factor recptor-2.Azide functionalized cell membrane acted as a platform for specific covalently coupling with alkynyl functionalized magnetic Fe_(3)O_(4)nanoparticles to prepare IOCMMNPs.The inside-out orientation of cell membrane was successfully verified by immunogold staining and sialic acid quantification assay.Ultimately,two compounds,senkyunolide A and ligustilidel,were successfully captured,and their potential antiproliferative activities were further testified by pharmacological experiments.It is anticipated that the proposed inside-out cell membrane coating strategy endows tremendous versatility for engineering cell membrane camouflaged nanoparticles and promotes the development of drug leads discovery platforms.

Perspectives and challenges of tropical medicinal herbs and modern drug discovery in the current scenario

Tropical diseases such as malaria, tuberculosis, trypanosomiasis, and leishmaniasis, account for a large number of deaths annually. Herbs are an excellent source of tropical medicines. Many advancements and discoveries have taken place in the field of drug discovery but still, a major population of tropical diseases relies on herbal traditional medicine. There are some challenges related to policy implementation, efficacy, resistance and toxicity of tropical medicines. There are many tropical diseases such as such as schistosomiasis, leishmaniasis, African sleeping sickness, filariasis and chagas disease which are neglected because very few pharmaceutical companies have shown their interest in developing therapeutics against these diseases of poor people. There are many benefits associated with herbal medicine such as the cost of production, patient tolerance, large scale availability, efficacy, safety, potency, recyclability, and environment friendly. A large number of natural extracts such as curcumin, artemisinin, morphine, reserpine, and hypericin, are in use for treatment of different tropical diseases for a long time. The current review is to discuss the overview of tropical medicinal herbs, its scope and limitations in the modern drug discovery process.

Recent progress in fragment-based drug discovery facilitated by NMR spectroscopy

Considerable developments have been observed in fragment-based lead/drug discovery(FBLD/FBDD)recently,with four drugs approved and many others under investigation.Nuclear magnetic resonance(NMR)has gained increasing popularity in FBLD due to its intrinsic capability in characterizing protein-ligand interactions in a large dynamic range of affinity,from weak hits to highly potent drugs.Here,we summarize NMR applications in fragment-based hit-to-lead evolution,including the construction of a fragment library,screening methods,spectra processing,and the delineation of the protein-ligand binding modes.These state-of-the-art NMR techniques have been exemplified in the discovery of inhibitors against multiple targets over the past five years,and they are expected to continue to provide new insights in the future.

硫化钠替代纯碱溶配苯胺黑药的新工艺研究与实践

七宝山铅锌矿的浮选流程为铅锌硫全优先浮选流程,其中,铅浮选采用以硫化钠、硫酸锌、亚硫酸钠为抑制剂,以苯胺黑药和乙硫氮为捕收剂的优先浮铅药剂制度。由于苯胺黑药的水溶性较差,长期以来,选厂用纯碱和苯胺黑药混合配药,以增加苯胺黑药的溶解性。为降低药剂成本、改善选矿指标,自2021年1月起,选厂改用硫化钠与苯胺黑药混合配药。该工艺于2020年12月完成实验室试验研究,2021年1月正式投入生产使用。连续使用两年,铅选矿回收率累计达65.15%,较2016~2020年累计指标64.50%提升了0.65个百分点;纯碱单耗由2016~2020年累计的70 g/t降为0 g/t,取得了良好的技术经济指标,是苯胺黑药配制工艺的重大突破,首创了硫化钠溶配苯胺黑药新技术。

先导化合物的发现——整合计算机虚拟筛选、化学合成和生物测试方法

先导化合物的发现在药物研究中起关键作用。基于分子对接的虚拟筛选是创新药物研究的新方法和新技术,已成为一种与高通量筛选互补的方法,广泛应用于先导化合物的发现中。本文结合本课题组的研究实例,综述了通过计算机虚拟筛选、化学合成和生物测试相结合的方法来发现先导化合物的研究工作。

计算机辅助药物设计在中药现代化中的应用

计算机辅助药物设计(CADD)是多学科交叉的边缘学科,在药物研发过程中起着枢纽作用,特别在先导化合物的发现和优化中发挥重要作用。中药现代化是当前我国中药产业发展之路,也是新药研发的有效途径。借助现代高新技术,特别是CADD技术,结合传统中医药理论进行中药研发,似可为中医药发展开辟一条适合我国国情的创新道路。本文主要探讨CADD在药物作用靶点的发现与验证以及中药现代化中的应用及其前景。

甘草对醋酸铅诱发小鼠精子畸形的抑制作用

目的 :观察中草药甘草对醋酸铅 [Pb (CH3COO) 2 ]诱发小鼠精子畸形的抑制作用。方法 :6 5只小鼠随机分成阴性对照组 (N· S)、阳性对照组 (MMC1.0 mg· kg- 1 )、 Pb (CH3COO) 2 诱变实验组 (4 0、 2 0和10 m g· kg- 1 ,相当于 1/ 3、1/ 6和 1/ 12 L D50 )、甘草诱变实验组 (1.2 5、 2 .5 0、 5 .0 0和 10 .0 0 g· kg- 1 ,相当于人 5×、10×、2 0×和 4 0×临床常用剂量 )、甘草抗诱变组 [(Pb (CH3COO) 2 2 0 mg· kg- 1 +甘草各剂量组 ) ],每组 5只动物。MMC和 Pb (CH3COO) 2 腹腔注射给药 ,其他药物均为灌胃给药 ,抗诱变实验组甘草和 Pb(CH3COO) 2 同时给药 ,每天 1次 ,连续 5 d。首次给药后 5周末 ,以颈椎脱臼法处死小鼠 ,取附睾 ,按 Wyrobek方法制片。结果 :甘草各剂量组 (1.2 5、 2 .5 0、 5 .0 0和 10 .0 0 g· kg- 1 )所诱发的小鼠精子畸形频率 (% ) (1.2 0± 0 .2 2、 1.38± 0 .2 7、1.5 2± 0 .2 5及 1.32± 0 .30 )与阴性对照组小鼠精子畸形频率 (1.2 8± 0 .18) %比较 ,差异无显著性 (P>0 .0 5 )。但甘草各剂量 (1.2 5、 2 .5 0、 5 .0 0及 10 .0 0 g· kg- 1 )与 Pb (CH3COO) 2 (2 0 mg· kg- 1 )一同给药时 ,可使Pb (CH3COO) 2 所诱发的小鼠精子畸形频率明显降低 ,即 (3.2 8± 0 .2

多靶向抗阿尔茨海默病的研究进展

阿尔茨海默病(AD)是一种以进行性认知功能减退为主要临床症状的慢性中枢神经系统退行性疾病,发病机制目前仍未完全阐明。AD是多种因素如淀粉样蛋白和tau蛋白聚集、过渡金属离子过量、氧化应激和乙酰胆碱水平低下等参与的复杂疾病。目前应用于抗AD临床治疗的药物多属于单靶向化合物,临床疗效不够理想。为此国内外医药研究者提出多靶向治疗AD的新策略,基于这一策略开发出同时能干预2个或多个作用于AD致病环节的化合物。现简要介绍这一多靶向抗AD新策略和一些多靶向化合物。

防阿片复吸先导化合物和新药的发现

根据国内外现有的研究结果,防海洛因复吸药物的研究主要集中在两个方面。其一是以阿片受体为靶标的防复吸药物研究,其二是以非阿片受体作用系统为靶标的防复吸药物研究。后者将成为防海洛因复吸药物的研究重点。

钙对出生前后低水平铅暴露大鼠学习记忆的影响

目的 :观察钙对出生前后低水平铅暴露大鼠学习记忆的影响 ,探讨低铅暴露早期干预的有效手段。方法 :将成年 Wistar孕大鼠随机分为正常组、染铅对照组和染铅加钙组 ,自母鼠孕 15 d至幼鼠 7w龄各组喂以相应饲料和饮水。实验大鼠 4 w龄时进行跳台试验 ,6 w龄时进行 Y迷宫试验 ,7w龄时检测全血铅、血清钙含量以及大脑、海马重量。结果 :实验大鼠血铅含量染铅对照组最高 ,染铅加钙组次之 ,正常组最低 ,血清钙含量正常组与染铅加钙组均高于染铅对照组 ;学习记忆成绩染铅加钙组好于染铅对照组 ,但低于正常组 ;实验未发现低铅染毒对实验大鼠大脑、海马重量的影响。结论 :低铅暴露尚不足以引起机体器官组织重量的改变 ,但生理功能已明显受到伤害 ,增加钙补充可明显改善铅暴露大鼠的学习和记忆能力 。

药物分子设计的策略:苗头和先导物的品质决定新药的成败

苗头化合物-先导物-候选药物是创制新药的三个重要里程碑,其中候选药物的确定是新药创制的关键环节,将创制过程分成研究和开发两个阶段,并且开发阶段所有环节都取决于候选药物的化学结构,所以决定了临床前和临床研究的命运。候选药物质量的高低又受制于先导化合物的类药性和苗头化合物的品质,苗头化合物演化成先导物是将新药的研究植根于有研发前景的结构上,先导物的优化是将活性化合物转化成候选药物的过程,是在药效、药代、安全性和物化性质等多维空间中的优化操作。本文结合实例讨论了发现苗头、确定先导物、先导物优化和确定候选药物的策略原则。

拼合原理及其在新药设计中的应用

新药研发的主要任务是药物先导化合物的发现以及先导化合物的结构优化。而结构拼合越来越成为设计和开发新药物先导化合物的重要方法之一,为新药的研制工作开创了一个新的局面。就目前有关结构拼合研究的基本理论、基本方法分类、发展趋势及其在研制新药的先导化合物中的应用实例进行了综述。

多中心药物临床试验中牵头单位的职责

在我国开展的多中心临床试验中要求必须有牵头单位牵头开展临床试验,可见牵头单位在临床试验中扮演着非常重要的地位,但"牵头单位"这一概念的形成却在国家出台的相关法规中无从查询,这就导致牵头单位的职责模糊不清,在实际实施过程中无法落实具体责任。研究认为,牵头单位作为临床试验的总负责单位,应全面掌握并监督临床试验的开展及试验的全部过程。而牵头单位中每个主体,即主要研究者、伦理委员会和机构办公室应认真履行好自己在各个环节中的职责。

中药醋制入肝减毒、增效现代研究

醋制是以醋为辅料炮制中药的方法统称,是体现中药炮制"增效减毒"的典型代表,其理论基础"醋制入肝"是指导中药炮制的基本理论之一。近些年来,学者围绕中药在醋制前后成分变化、药效学机制、药代动力学方面进行了大量研究,有力地推动了对"醋制入肝"理论的科学阐释。从醋制减毒、增效角度就近些年来醋制中药研究进展进行综述,并对目前研究中存在问题进行分析,提出了"醋制入肝"机理研究的思路,以期为深入开展"醋制入肝"理论研究提供参考。

祛风及开窍类引经药对六味地黄丸有效成分眼内分布的影响

目的观察祛风及开窍类引经药柴胡、防风及冰片对六味地黄丸有效成分在眼不同组织分布和代谢的影响,探讨引经药是否可以增加药物有效成分在眼部的靶向性聚集。方法将252只家兔随机分为6组,每组42只,对照组正常饲养不作处理,其它组分别用蒸馏水、六味地黄丸、六味地黄丸+防风、六味地黄丸+柴胡、六味地黄丸+冰片溶液灌胃,在灌胃后0.25、0.50、0.75、1.00、2.00、4.00、8.00 h各时间点每组随机取6只家兔,采用液质联用技术检测房水、玻璃体、视网膜中莫诺苷和马钱苷的含量,比较各组含量差异。结果房水中检测发现莫诺苷、马钱苷的浓度曲线变化趋势较一致,均在灌胃后0.25~1 h达到峰值,在8 h后基本清除完全,其中六味地黄丸+冰片组的马钱苷、莫诺苷的浓度在0.25~0.75 h均较六味地黄丸组、六味地黄丸+防风组、六味地黄丸+柴胡组高,差异有统计学意义(P<0.05)。各组有效成分在玻璃体中的浓度均很低,马钱苷的曲线呈波动趋势,各个时间点各组两两比较差异均无统计学意义(P>0.05),莫诺苷的曲线在0.25~1 h达到峰值,随后在8 h基本清除完全,其中六味地黄丸+冰片组的莫诺苷浓度在0.25~0.75 h均较六味地黄丸组、六味地黄丸+防风组、六味地黄丸+柴胡组高,差异有统计学意义(P<0.05);其它各组两两比较,差异均无统计学意义(P>0.05)。各组视网膜内莫诺苷和马钱苷的浓度也偏低,其中六味地黄丸+冰片组马钱苷和莫诺苷的浓度在0.25 h较六味地黄丸组、六味地黄丸+防风组、六味地黄丸+柴胡组高,差异有统计学意义(P<0.05);其他组两两比较,差异均无统计学意义(P>0.05)。结论冰片可以增加六味地黄丸有效成分在房水、玻璃体和视网膜的浓度,这可能是引经药的作用机制之一。

杭白菊总黄酮对铅诱导小鼠氧化损伤的拮抗效应研究

目的:探讨杭白菊总黄酮(total flavonoids from Chrysanthemum morifolium,TFCM)对铅诱导小鼠脑、肝脏和肾脏氧化损伤的拮抗效应。方法:将90只雄性小鼠分为9组:正常组,模型组,阳性药组,TFCM低、中、高(150,300,500 mg.kg-1)剂量组,TFCM低、中、高剂量+二巯基丁二酸(DMSA,70 mg.kg-1)组。前20 d,除正常组外,其余小鼠隔天腹腔注射醋酸铅建立铅中毒模型;接下来的10 d,各组小鼠灌胃给予受试物。实验结束后,摘眼球取血及各脏器,测定全血、脑、肝脏、肾脏中铅、锌和铜的含量,计算脏体比重系数,并对抗氧化酶活性及脂质过氧化水平进行检测和分析。结果:TFCM可拮抗铅中毒小鼠体重的下降和脏体比重的升高。单独使用TFCM对小鼠血液及组织中铅浓度并无显著影响,但与DMSA联合使用时排铅效果显著(P<0.01),且未造成锌、铜的流失。中、高剂量TFCM在增加小鼠脑GSH含量,GSH-Px,SOD,CAT活性及降低MDA含量方面,效果明显优于DMSA;高剂量TFCM在增加小鼠肝脏和肾脏GSH-Px,CAT活性及降低MDA含量方面,效果也明显优于DMSA。TFCM与DMSA联合使用时,也可显著改善小鼠脑、肝脏和肾脏脂质过氧化,增加GSH,GSH-Px,SOD和CAT的活性,效果优于单独使用DMSA。结论:TFCM可显著提高铅中毒小鼠组织中抗氧化酶的活性,改善脂质过氧化,从而明显拮抗铅诱导的脑、肝脏和肾脏氧化损伤。

银苓Ⅰ号对铅中毒小鼠非特异免疫功能的影响

目的:探讨中药复方银苓Ⅰ号对铅中毒小鼠非特异免疫功能的影响。方法:小鼠自由饮用醋酸铅溶液造模,分别予银苓Ⅰ号或依地酸钠钙治疗3周;观察外周血弊细胞计数、碳粒廓清指数K及校正指数α、免疫脏器指数等非特异性免疫功能指标的变化。结果:银苓Ⅰ号对外周血白细胞计数、碳粒廓清指数K及校正指数α、免疫脏器指数有明显改善作用,而且碳粒廓清能力优于依地酸钠钙。结论:银苓号可在一定程度上对抗铅中毒所致的非特异免疫损害,效果优于依地酸钠钙。