代谢物组学在医药研究中的应用

代谢物组学(metabonomics)是一门新兴"组学"(omics)学科,它从整体角度研究代谢物组"图谱",能够直接了解一个样品当前的生理或生化状态,获得与其他"组学"学科十分不同,又相当有意义的信息.代谢物组学在医药研究中,从新药研发到临床应用甚至其后的所有方面都有用,有希望发展成为药物研制和开发的必要组成部分.现概述代谢物组学在新药筛选、药物作用机制研究、个体化用药研究方面的应用.     

药物微生物组在新药研发中的应用

药物基因组学研究宿主基因层面对药物安全性与有效性的作用,指导新药研发过程。但宿主基因层面不能完全解释个体间药效差异。药物微生物组学是药物基因组学的重要扩展,研究肠道微生物对药物安全性与有效性的影响。目前与肠道微生物相关的大数据、多组学分析、粪菌移植、合成生物学等学科与技术已逐步在新药研发中应用,本文综述了新药研发的现状以及肠道微生物与药物相互作用,概括了目前肠道微生物相关药物的研发进展。     

代谢物组学在新药研究中的应用研究进展

代谢物组学是近5年来发展起来的与基因组学、蛋白质组学等并列的学科。它运用核磁共振等分析技术，测定细胞和体液中内源性或外源性代谢物的经时变化，评价细胞功能和生物体的病理生理状态。本文综述其在新药开发中的作用。     

基于反向转录组学的新药研发策略

反向转录组学是基于化合物与疾病转录组特征的反向匹配,计算筛选发现活性化合物的新药研发策略.本文介绍了反向转录组学的基本原理和经典实例,并阐述了实施该策略的一般流程和关键环节.     

代谢组学在药学中的应用

代谢组学是继基因组学和蛋白质组学之后发展起来的一种研究生物系统的组学方法。通过分析生物体液及组织中所有小分子物质以研究有机体内物质代谢规律和健康状况。代谢组学是新药研究开发的重要组成部分,本综述就代谢组学与药学研究的关系、代谢组学用于药学研究的特点和优势及其在药物研究中的应用等相关的问题进行阐述。     

代谢组学技术在抗结核新药研发中的应用研究进展

目的:了解代谢组学技术应用于结核分枝杆菌(MTB)代谢物及代谢途径检测的研究情况,为开发治疗耐药MTB感染的安全新药提供参考。方法:以"结核分枝杆菌""代谢组学""药物靶点""药物研发"等的中英文为关键词,在PubMed、中国知网、维普等数据库中组合检索2012年-2018年6月发表的相关文献,并从抗结核药物的新靶点(包括MTB脂代谢、能量代谢、氨基酸代谢、miRNA等途径)、新抗菌化合物的筛选(主要是抑制MTB呼吸链的抗菌化合物)及抗结核新药的临床前评价等3个方面总结代谢组学技术应用于抗结核新药研发的研究进展。结果与结论:共获得相关文献948篇,其中有效文献40篇。应用代谢组学技术研究发现,干扰脂代谢途径的相关酶或基因等(如分枝菌酸、乙酰辅酶A羧化酶、脂酰辅酶A合成酶、泛酸等),干扰能量代谢的异柠檬酸裂解酶,抑制氨基酸代谢途径中的色氨酸合成代谢途径、β-碳酸酐酶合成途径、丙酮酸激酶相关途径,抑制miRNA调控途径等均可作为抗结核药物研发的新作用靶点。通过代谢组学技术已经发现细胞色素bc1复合物QcrB的抑制剂Q203、QOAS,腺苷三磷酸合酶FoF1-ATP抑制剂,细胞色素AtpE抑制剂BDQ,二芳基喹啉(DARQS)等呼吸链抑制化合物,以及腺苷酸合成酶MbtA抑制剂、还原型辅酶Ⅰ脱氢酶Ⅱ抑制剂、蛋白酶ClpP和膜蛋白复合体3的抑制剂、脂肪酰基-腺苷一磷酸(AMP)连接酶FadD32和聚酮合成酶的抑制剂等抗菌化合物。应用代谢组学技术分析药物作用后机体的代谢变化,可为抗结核药物的毒性、安全性、疗效等评价提供技术手段。但目前对于代谢组学技术所获数据的处理方法尚不完善,数据分析模型尚需进一步完善与优化;此外,国内对代谢组学技术应用于抗结核药物研发的研究范围较窄,且易漏掉对不稳定的小分子和大分子代谢物的分析,因此需结合蛋白质组学或转录组学以更高效、准确地为抗结核新药研发提供支持。     

代谢组学在药物毒理学中的应用

代谢组学是利用多元统计分析方法对特定条件下的某个生物系统（细胞,组织,器官）的所有代谢产物进行研究从而探索特异性的生物标志物和代谢途径的新兴学科。本文就代谢组学在药物毒理学中的应用进行了简要评述,并对现阶段代谢组学在药物毒理学研究中存在的问题和发展趋势进行了探讨。     

代谢组学在中医气虚研究中的应用

目的为代谢组学在中医气虚体质及其治疗药物研究中的应用提供参考。方法通过检索国内外数据库中的相关文献,对近年来代谢组学在气虚研究中的运用进行归纳和总结。结果代谢组学的研究思路与中医学相似,在中医气虚治疗研究中通过分析代谢产物对相关疾病标志物进行筛选,可为新药的研究提供潜在治疗靶点。对气虚患者用药前后的代谢产物进行分析,可明确药物作用机制并科学地评价药效。在中医证候诊断研究中,代谢组学在认识虚证本质方面提供了科学依据。人参对气虚证有显著的疗效,但人参对气虚体质的调节作用机制尚不明确。结论运用代谢组学技术可寻找气虚体质人群经干预后特异代谢产物的变化,寻找潜在的生物标志物,通过调节体内代谢达到预防、治疗疾病以及相关药品的开发等目的。     

代谢组学在肝肾损伤研究中的应用

代谢组学是近年来新发展起来的一门组学,已成为生物医学研究领域的新热点.由于其广泛的应用前景,目前已是系统生物学的重要组成部分.肝损伤及肾损伤是临床常见的危害人类健康的疾病,但目前的指标缺乏特异性,且灵敏度不高,造成临床上难以对肝肾损伤做出准确而及时的预警和监测.代谢组学能从代谢的角度整体分析疾病,快速、安全地对疾病的严重程度进行判别,在肝肾损伤的早期诊断等方面的研究已初显优势.本文主要综述了代谢组学技术在肝肾损伤研究中的应用现状.     

代谢物组学在肾病研究中的应用

肾功能经典生化指标缺乏足够的灵敏度和专属性,明显滞后于肾病的发生,在预测肾病进程风险及指导治疗干预方面尚有欠缺。因此,筛选更灵敏、专属的肾病相关生物标志物具有重要意义。代谢物组学以其独特的研究思路和技术优势,在肾病的临床诊断、预后评估和个体化治疗方面初步显示出应用潜能。本文就代谢物组学相关技术在肾病研究领域的最新进展和应用前景做简要综述。     

Advances in flow cytometry for drug screening

Importance of the field: Flow cytometry is considered today as a mature technology. Recently, it has become an accurate tool for screening applications. Yet, not many studies have been published emphasizing flow cytometry as a tool of choice for drug screening except multiplex bead assay.

Areas covered in this review: Scanning the literature for technology breakouts in screening by flow is not an easy task. When a private industry has an accurate and fast screening technology on hands, why should they make public a tool precious for their screening applications? On the European academic side, there are regrettably few grants to help develop and publish screening methodologies. So, a less scientific way to find out is a close market survey seeking new instruments and associated kits or new methods. From here, can one expect flow cytometry to be a tool with new potential for drug discovery?

What the reader will gain: As the machines are getting simpler to use, a need for plug-and-analyze software has emerged. New analysis tools remain an important step as they will permit to analyze and compare several parameters in a multi-well format simultaneously and this for several cell types for cytomics: a multiparametric, dynamic approach to cell research as cytomics has a practical role to play in drug discovery within the immediate limitations of cell-based analyses.

Take home message: Developing new software with multi-well comparison capabilities and most importantly real-time interaction on cytograms can easily circumvent the lack of fluorescent channels on small bench top machines.     

The development of high-content screening (HCS) technology and its importance to drug discovery

ABSTRACT

Introduction: High-content screening (HCS) was introduced about twenty years ago as a promising analytical approach to facilitate some critical aspects of drug discovery. Its application has spread progressively within the pharmaceutical industry and academia to the point that it today represents a fundamental tool in supporting drug discovery and development.

Areas covered: Here, the authors review some of significant progress in the HCS field in terms of biological models and assay readouts. They highlight the importance of high-content screening in drug discovery, as testified by its numerous applications in a variety of therapeutic areas: oncology, infective diseases, cardiovascular and neurodegenerative diseases. They also dissect the role of HCS technology in different phases of the drug discovery pipeline: target identification, primary compound screening, secondary assays, mechanism of action studies and in vitro toxicology.

Expert opinion: Recent advances in cellular assay technologies, such as the introduction of three-dimensional (3D) cultures, induced pluripotent stem cells (iPSCs) and genome editing technologies (e.g., CRISPR/Cas9), have tremendously expanded the potential of high-content assays to contribute to the drug discovery process. Increasingly predictive cellular models and readouts, together with the development of more sophisticated and affordable HCS readers, will further consolidate the role of HCS technology in drug discovery.     

High-throughput flow cytometry for drug discovery

High-throughput flow cytometry exploits a novel many-samples/one-file approach to dramatically speed data acquisition, limit aspirated sample volume to as little as 2 μl/well and produce multisample data sets that facilitate automated analysis of samples in groups as well as individually. It has been successfully applied to both cell- and microsphere-based bioassays in 96- and 384-well formats, to screen tens-of-thousands of compounds and identify novel bioactive structures. High-content multiparametric analysis capabilities have been exploited for assay multiplexing, allowing the assessment of biologic selectivity and specificity to be an integral component of primary screens. These and other advances in the last decade have contributed to the application of flow cytometry as a uniquely powerful tool for probing biologic and chemical diversity and complex systems biology.     

Promise and challenges in drug discovery and development of hybrid anticancer drugs

Background: Because cancer is a complex disease, it is unlikely that a single mono functional ‘targeted’ drug will be effective for treating this most advanced disease. Combined drugs that impact multiple targets simultaneously are better at controlling complex disease systems, are less prone to drug resistance and are the standard of care in cancer treatment. In order to improve the efficiency of using a two-drug cocktail, one approach involves the use of the so-called hybrid drugs, which comprises the incorporation of two drugs in a single molecule with the intention of exerting dual drug action.

Objective: In the present article, we discuss the design, synthesis and various applications of anticancer hybrid agents and the developments in this field during the last few decades. Additionally, we describe different types of linkers and their role in contributing towards biological effects and the in vivo mechanism of drug release. We also depict some challenges from scientific and regulatory perspectives in the hybrid drug development process.

Conclusion: In the era of increasing drug resistance in cancer patients, the discovery of hybrid drugs could provide an effective strategy to create chemical entities likely to be more efficacious and less prone to resistance. However, some technical and regulatory challenges will have to be surmounted before hybrid drugs succeed in the clinical settings and justify the considerable promise of this novel concept.     

High-throughput and in silico screenings in drug discovery

Background: In the current situation of weak drug pipelines, impending patent expiration of several blockbuster drugs, industry consolidation and changing business models that target special diseases like cancer, diabetes, Alzheimer's and obesity, the pharmaceutical industry is under intense pressure to generate a strong drug pipeline distinguished by better productivity, diversity and cost effectiveness. The goal is discovering high-quality leads in the initial stages of the development cycle, to minimize the costs associated with failures at later ones. Objective: Thus, there is a great amount of interest in further developing and optimizing high-throughput screening and in silico screening, the two methods responsible for generating most of the lead compounds. Although high-throughput screening is the predominant starting point for discovery programs, in silico methods have gradually made inroads by their more rational approach, to expedite the drug discovery and development process. Conclusion: Modern drug discovery strategies include both methods in tandem or in an iterative way. This review primarily provides a succinct overview and comparison of experimental and in silico screening techniques, selected case studies where both methods were used in concert to investigate their performance and complementary nature and a statement on the developments in experimental and in silico approaches in the near future.     

Improving attrition rates in Ebola virus drug discovery

Introduction: The Ebola 2014/2015 outbreak has had devastating effects on the people living in West Africa. The spread of the disease in endemic countries and the potential introduction of sporadic cases in other continents points out the global health threat of Ebola virus disease (EVD). Despite the urgent need for treating EVD, there are no approved treatments. Given the lack of treatments available, alternative therapeutic strategies have had to be used.

Areas covered: This article summarizes the unregistered therapeutics that were used to treat patients during the Ebola 2014/2015 outbreak, in addition to approaches used for the selection of candidate drugs. The article also proposes potential theoretical criterion for use in virtual screening of molecular libraries for candidate Ebola drugs.

Expert opinion: In the absence of approved therapeutics for EVD, experimental drugs have had to be used. The repurposing of approved drugs for the treatment of EVD, as an alternative therapeutic strategy, has also been suggested. Screening in vitro- and in silico-approved drugs revealed several promising candidates but further testing is required to test their efficacy. All these therapeutic approaches are, however, only short-term solutions and there is still an urgent need for the development of specific drugs for the current and future outbreaks.     

Application of porcine gastrointestinal organoid units as a potential in vitro tool for drug discovery and development

The gastrointestinal tract (GI) is a crucial part of the body for growth and development and its dysregulation can lead to several diseases with detrimental effects. Most of these diseases lack effective treatment, occurring as a result of inappropriate models to develop safe and potent therapies. Organoids are three‐dimensional self‐organizing and self‐renewing structures that are composed of a cluster of different cells in vitro that resemble their organ of origin in architecture and function. Over recent years, organoids have been increasingly used to study developmental biology, disease progression, i.e., cancer, tissue engineering and regenerative medicine and other biological processes. Owing to their complex nature and ability to retain the morphological and molecular patterns of their tissue‐of‐origin, they have great potential as alternative tools/models for drug screening, development and biomarker discovery. Using a species with similar genetic homology to humans as a source of organoids, such as the porcine model may offer huge translational relevance. This review focuses on the culture and establishment of porcine organoid units and their potential use and application as in vitro models to further the science of drug discovery, by overcoming current limitations of established two‐ and three‐dimensional models. It also highlights the translational application of using porcine organoids as a model of different disease contexts.     

Tools for GPCR drug discovery

G-protein-coupled receptors (GPCRs) mediate many important physiological functions and are considered as one of the most successful therapeutic targets for a broad spectrum of diseases. The design and implementation of high-throughput GPCR assays that allow the cost-effective screening of large compound libraries to identify novel drug candidates are critical in early drug discovery. Early functional GPCR assays depend primarily on the measurement of G-protein-mediated 2nd messenger generation. Taking advantage of the continuously deepening understanding of GPCR signal transduction, many G-protein-independent pathways are utilized to detect the activity of GPCRs, and may provide additional information on functional selectivity of candidate compounds. With the combination of automated imaging systems and label-free detection systems, such assays are now suitable for high-throughput screening (HTS). In this review, we summarize the most widely used GPCR assays and recent advances in HTS technologies for GPCR drug discovery.