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2019全国老年痴呆与认知障碍相关疾病学术大会

作者： ZHOU Wen-xia Beijing Institute of Pharmacology and Toxicology State Key Laboratory of Toxicology and Medical Countermeasures

The unbalance between synaptic(GluN2 A,mediating the protective pathway) and extrasynaptic NMDA receptors(NMDARs)(GluN2 B,mediating the excitotoxic pathway) has been found in Alzheimer disease(AD),indicating restoring the balance of GluN2 A and GluN2 B should be beneficial for AD therapy.In this study,the GluN2 B-selective antagonist,ifenprodil,and the non-selective NMDAR agonist,NMDA,had little effects on amyloid-beta(Abeta)-induced long-term potentiation(LTP) deficits.Enhancing the activity of GluN2 A had a protective effect against Abeta,and specific activation of GluN2 A and inhibition of GluN2 B showed a better protective effect.The combination of ifenprodil and D-cycloserine(a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests than ifenprodil or D-cycloserine alone,meanwhile,the combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone.These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Abeta-induced neurotoxicity,suggesting that modulation of the balance between GluN2 A and GluN2 B might be a good strategy for Drug discovery against AD.

关键词： Alzheimer disease GluN2A GluN2B ifenprodil D-cycloserine Drug discovery

Metabolomics and Its Potential in Drug discovery and Development From TCM

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World Journal of Traditional Chinese Medicine 2015年第4期1卷 26-32页

作者： Hang Chu Ai-Hua Zhang Ying Han Xi-Jun Wang National TCM Key Lab of Serum Pharmacochemistry Key Laboratory of Metabolomics and Chinmedomics Department of Pharmaceutical AnalysisHeilongjiang University of Chinese Medicine

Metabolomics, an omic science in systems biology, is the comprehensive profiling of metabolic changes occurring in living systems and has been widely used in the modern research of traditional Chinese medicine(TCM). TCM is a complex medical science, which reflects rich philosophical dialectical thought, puts the human body into a large system for observation and keeps human in a healthy status. For TCM aroused great interest in the whole world, herbs and Chinese medical formulae(CMF) as treatment methods have also been widely attention.Metabolomics represents a powerful way that provides a dynamic drawing of the phenotype of biological systems via the research of endogenous metabolites, and its methods are similar to those of TCM. This review summarizes the advantages of metabolomics, highlight the key role of biomarkers for Drug discovery and development of TCM.

关键词： Metabolomics traditional Chinese medicine formulae biomarker Drug discovery

Protein targets for structure-based antiMycobacterium tuberculosis Drug discovery

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Protein & Cell 2010年第5期1卷 435-442页

作者： Zhiyong Lou Xiaoxue Zhang Laboratory of Structural Biology Tsinghua UniversityBeijing 100084China Higher Education Press Beijing 100029China

Mycobacterium tuberculosis,which belongs to the genus Mycobacterium,is the pathogenic agent for most tuberculosis(TB).As TB remains one of the most rampant infectious diseases,causing morbidity and death with emergence of multi-drug-resistant and extensively-drugresistant forms,it is urgent to identify new drugs with novel targets to ensure future therapeutic success.In this regards,the structural genomics of M.tuberculosis provides important information to identify potential targets,perform biochemical assays,determine crystal structures in complex with potential inhibitor(s),reveal the key sites/residues for biological activity,and thus validate drug targets and discover novel drugs.In this review,we will discuss the recent progress on novel targets for structure-based anti-M.tuberculosis Drug discovery.

关键词： Mycobacterium tuberculosis crystal structure Drug discovery target

Patient-derived xenograft models for oncology Drug discovery

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Journal of Cancer Metastasis and Treatment 2015年第1期1卷 8-15页

作者： Gang Li Ignyta Inc. San DiegoCA 92121USA.

The success of targeted therapies for cancer patients rests on three major components:the right target(s),the right drug and drug combination,and the right patient population.Although much progress has been made in understanding the mechanism of disease and in refi ning pharmaceutical properties of therapeutic agents,the attrition rates between target discovery and drug marketing approval have been high,especially in oncology.One of the main reasons underlying this undesirable statistics is believed to be the lack of predictive power of the model systems used in the preclinical setting.Several strategies have been employed with the aim of improving the predictive value of the preclinical studies,such as incorporating genomic profi ling and molecular segmentation into model selection,and enhancing the development and application of patient-derived xenograft models even during early stage of Drug discovery.This brief review will summarize some of the recent concept and practice in incorporating patient-derived models into all stages of Drug discovery process,from target to clinical development.

关键词： Animal models Drug discovery oncology patient-derived xenograft translational research

Drug discovery based on natural products by using chemical biology approach

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Drug Discovery based on natural products by using chemical b...

中国生物化学与分子生物学会第十二届全国会员代表大会暨2...

作者： Hualiang Jiang Drug discovery and Design Center State Key Laboratory of Drug ResearchInstitute of Materia MedicaChinese Academy of Sciences

Drug discovery,from its traditional area of lead discovery and optimization,has extended toward two directions: upstream for target identification and validation,and downstream for preclinical study.Both directions are associated with discovering new pathogenic pathways or re-evaluating existing pathways.Chemical biology is a new discipline to fulfill such kind of task.We will demonstrate how to identify potential drug targets and related pathwaysusing active natural compounds as probes.Targeting the discovered acting pathway we optimized the natural products to obtained drug candidates.

关键词： Drug discovery Natural products Chemical biology

Rapid Construction of Alkynylamide-substituted α,β-Diamino Acid Derivatives for Drug discovery

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Rapid Construction of Alkynylamide-substituted α,β-Diamino...

第十届全国化学生物学学术会议

作者： Ruirui Lei Jie Yu Kaili Jia Suzhen Dong Wenhao Hu Shunying Liu Shanghai Engineering Research Center of Molecular Therapeutics and New drug Development East China Normal University

Alkyne moieties widely exist in natural products isolated from plants and marine organisms and pharmaceuticals as important pharmacophores. Developing straightforward and convenient approaches to rapid access to complex molecules containing alkynes is in increasing demand. Here, we reported a rapid approach to alkynylamide-substituted α,β-diamino acid derivatives from simple staring materials（Scheme 1） by using our previous developed multi-component method. [1] The desired products were obtained in high yields and with high diastereoselectivity. The resulting products showed a wide range of good bioactivity for cancer cells in the phenotypic screening（Table 1 and Figure 1） and are promising used as hits in Drug discovery.

关键词： Alkyne α,β-Diamino acid derivatives Multi-component method Drug discovery

The Neuroimmunopharmacology of Psychoactive Substances and CNS Drug discovery

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The Neuroimmunopharmacology of Psychoactive Substances and C...

第十届全国化学生物学学术会议

作者： Xiaohui Wang Chemical Biology Laboratory Changchun Institute of Applied Chemistry Chinese Academy of Sciences

drug addiction is a serious problem, which causes serious medical and social problems.Currently there is no effective way for treating drug addiction, especially for synthetic drug abuse. Most drug abuse research have been concentrated on neurons in the central nerve system（CNS）, however, the action of glia, which accounts for 90% cells in CNS, have been long neglected. We have recently discovered that the psychoactive substances（including opioids, cocaine and methamphetamine） activate microglia. This xenobiotic associated molecular pattern（XAMP）-induced microglia activation occurs through a novel pathway that depends on TLR4. TLR4 activation causes microglia to release pro-inflammatory factors,which modulate the neural circuitry of drug reward and contribute to drug dependence and addiction. Therefore, TLR4 is a good Drug discovery target for developing "all-purpose"therapeutics for treating various types of drug addiction. A series of TLR4 antagonists have been discovered by multiple Drug discovery strategies for treating drug abuse.

关键词： Drug discovery drug abuse Toll-like receptor 4 microglia

Zebrafish-based natural product Drug discovery

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Zebrafish-based natural product drug discovery

第一届《药学学报》药学前沿论坛暨2015年中国药学会中...

作者： LI Chun-qi XU Yi-qiao LIU Hong-cui ZHU Xiao-yu LAN Xiao-hong LAO Qiao-cong ZHANG Yong Hunter Biotechnology Corp. Institute of Watershed Science and Environmental Ecology Wenzhou Medical University

Zebrafish as a vertebrate animal model is increasingly used for in vivo Drug discovery and for assessing drug toxicity and safety.Numerous studies confirm that mammalian and zebrafish physiology,development,metabolism and pathways are strikingly similar and zebrafish is extremely predictive of mammalian responses.This convenient and predictive animal model offers several compelling experimental advantages including transparency,high throughput,short test period,low cost,small amount of compound required,easy manipulation and direct compound delivery,et al.FDA and EMEA have accepted zebrafish toxicity and safety assessment data for IND approval and more than one dozen of new drugs including natural products discovered primarily based on zebrafish model are now in clinical trials.In this reivew,we will introduce:① the background of zebrafish-based natural product Drug discovery;② zebrafish models for assessing natural product toxicity and safety including acute toxicity,LC,development toxiciy & teratogenicity,cardiovascular toxicity,liver toxicity,nerve toxicity,behavior toxicity,blood toxicity,anaphylactoid reaction and so on;③ zebrafish models of human diseases for natural product Drug discovery including anti- and pro-angiogenesis models,cancer models,cardiovascular disease models,CNS disease models,liver and metabolic disease models,inflammatory and bone disease models,and so on;④zebrafish models and assays for traditional Chinese medicine(TCM),TCM biologically quality control,TCM processing optimization and native Chinese herb identification.Zebrafish Drug discovery platform can reduce the time and cost required for the natural product drug development process.

关键词： zebrafish natural product toxicity Drug discovery

Pharmacology and Drug discovery

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中国药理学与毒理学杂志 2019年第10期33卷 754-754页

作者： SJ ENNA Departments of Physiology and of Pharmacology University of Kansas Medical Center

There are two general approaches to Drug discovery. The oldest is the empirically-driven in vivo identification of a drug candidate, with little or no consideration given to identifying the active constituent. The alternative is mechanism-based, a process that entails the in vitro screening of purified chemical compounds to identify those that interact specifically with a selected biological target, after which they are tested for therapeutic potential. A major difference between these approaches is the extent to which the principles of pharmacology are employed to demonstrate safety and efficacy and to enable improvements in the therapeutic properties of the product. As a thorough pharmacological analysis of the pharmacokinetics and pharmacodynamics of a test agent requires that it be a stable, single, purified substance, such testing is more difficult with unpurified samples containing multiple compounds as compared to single agents. A lack of pharmacological information compromises the clinical utility of a test substance by leaving open questions about its bioavailability, metabolism, and mechanisms of therapeutic actions and toxicities. Although Drug discovery success has be achieved with both the empirically-driven and mechanism-based approaches, the proper application of pharmacological techniques in the Drug discovery process maximizes efficacy, safety and the chance for regulatory approval. In addition, pharmacological data provides information needed for improving the therapeutic properties of an agent, enhancing its clinical utility, and extending the product lifespan.

关键词： pharmacological techniques Drug discovery mechanism-based approaches