六种药物新靶点的研究

某些疾病用药后往往疗效低、易复发，原因在于治疗药物未能直抵病灶——药物靶点。以下为六种药物新靶点初探。     

肿瘤药物治疗的新靶点研究进展

肿瘤是多个病因、多阶段、多基因的长期过程。寻代肿瘤相关基因并以此为靶点已成为肿瘤治疗的新手段。本文综述了两种细胞周期相关激酶,细胞生存有关的Ａｋｔ和ＩＧＦ１Ｒ,细胞凋亡抑制因子及与肿瘤生长浸润转移有关的粘附分子等的作用,并讨论以此为靶点治疗肿瘤的可行性。     

抗肿瘤药物新靶点与新药研究

抗肿瘤药物新靶点包括蛋白激酶、细胞周期和凋亡调节基因、蛋白法尼基转移酶、组蛋白去乙酰化酶和端粒酶。综述这些靶点及其相应药物近年来的研究进展。     

mPGES-1——一个新的药物开发靶点

综述膜结合型前列腺素E2合酶-1（mPGES-1）的生物学性质、生理和病理作用,以及将其作为一个新的药物作用靶点用于药物开发的可能性。mPGES-1是3种前列腺素E2合酶之一,属于诱导型表达的酶,能被致炎因子诱导而大量表达,在多种疾病,如关节炎、炎症相关性发热和疼痛、动脉粥样硬化及癌症的病理生理过程中均发挥着重要作用。     

药物研究开发、生产及销售——最新版Pharmaprojects鉴定了1300种蛋白作为药物靶点

英国PJB出版社出版的Pharmaprojects研发数据库公布的最新消息称，到目前为止已有超过1300种特异的蛋白被鉴定为潜在的药物治疗靶点，其中包括1200多种人类特有的蛋白。     

抗肿瘤药物新靶点

恶性肿瘤是危害人们生命健康的重大疾病,2005年全世界有760万人死于肿瘤,其中中国有160万。目前我国有约220万肿瘤患者,抗肿瘤药物的研发任重而道远。近年来,随着肿瘤生物学及相关学科的飞速发展,人们逐渐认识到细胞癌变的本质是细胞信号转导通路的失调导致的细胞无限增殖,随之而来的是抗肿瘤药物研发理念的重大转变。研发的焦点正在从传统细胞毒药物转移到针对肿瘤细胞内异常信号系统靶点的特异性新一代抗肿瘤药物。不同于传统细胞毒药物选择性差、毒副作用强、易产生耐药性等特点,靶点特异性抗肿瘤药针对于正常细胞和肿瘤细胞之间的差异,…     

抗心律失常药物的新靶点及新药研发

正常心脏功能依赖于适当而规律的心跳速率(心率).当心率太快或太慢时,心脏功能可能发生障碍,伴随着从轻度乃至危及生命并发症的可能.过去,依靠药物治疗心律失常很困难因为缺乏有效性同时又伴有高风险的并发症.一些最新进展为开发新型的、优越的心律失常治疗方法开辟了令人振奋的可能性.文章就药物治疗心房颤动及心室颤动两种常见心律失常的最新进展和前景进行综述.     

类风湿性关节炎新靶点药物治疗进展

类风湿性关节炎是一种病因未明的慢性系统性疾病,目前临床上对此类患者的治疗主要以药物治疗为主。本文通过介绍小分子化学合成类药物、JAK抑制剂、靶向IL-17药物,以探讨类风湿性关节炎靶点药物的作用机制及其治疗进展情况,旨在为临床治疗类风湿性关节炎提供新的方向。     

Aphoenix公司公布新药物靶点资料

日本生物投资公司Aphoenix已开发出一种“逆靶向”技术,该技术可发现未知作用机制小分子药物的结合蛋白。该专利平台已应用于几个新型化合物,Aphoenix公司正为这几个化合物寻求合作伙伴。     

RNAi药物研究进展

干扰RNA(RNAi)是核酸药物的分支,也被称为小核酸药物,一般来说包括小干扰RNA(siRNA)和微小RNA(miRNA)两类.因为其具有基因靶向性强、开发周期短、候选靶标丰富等特点,而受到广泛的关注;但另外一方面,RNAi药物也具有核酸类药物的通常缺点:生物稳定性差、易被降解、给药系统设计比较困难等.这些缺点成为制...     

MmpL3 a potential new target for development of novel anti-tuberculosis drugs

Introduction: Tuberculosis (TB) is still a leading cause of mortality in the developing world and there is an unmet clinical need for new drugs with novel mechanism of action. Targeting the complex and unique cell wall of TB-causing pathogen Mycobacterium tuberculosis (Mtb) has been a mainstay of TB drug discovery. Though, the composition of the cell wall of Mtb is well understood, little is known about the assembly process of the cell wall such as the transport of mycolic acids across the cell wall.

Areas covered: Recent research demonstrating MmpL3 protein as a transmembrane transporter of mycolic acids is discussed. In addition, MmpL3 has also been implicated in heme transport. Research describing several diverse chemical inhibitors that inhibit MmpL3 is reviewed.

Expert opinion: Evidence so far suggests MmpL3 is a transporter of mycolic acids. It has emerged as a novel therapeutic target for Mtb that is essential and for which several small molecule inhibitors have been identified. Identifying the interacting partners, understanding the substrate specificity and the mechanism of transport by MmpL3 are some of the gaps in knowledge that need to be addressed.     

用于新药筛选的药靶的研究进展

目的讨论选择正确的药靶在新药研发过程中的重要性。方法作者以近年来发表的21篇中外文献为依据,以细胞膜G蛋白偶合受体、生长因子受体、细胞膜离子通道蛋白、细胞核受体为例,介绍药靶的筛选、确认以及在此基础上筛选出的代表性药物。结果与结论随着分子遗传学、功能基因组学、蛋白质组学和生物信息学的快速进展,越来越多的功能清楚的生物学分子正在被发现,这其中的某些基因及其产物由于被证明与疾病发生和发展相关而成为分子药靶,选择正确的药靶在新药研发过程中具有重要作用。     

药物靶标研究中的功能基因组学

在人类基因组计划完成以及新的生物技术推动下,传统的药物发现模式正在向基因组学为基础的现代药物发现模式转变。药物靶标的发现,是药物发现途径中最关键的一个环节。该文就目前靶标不同阶段的研究策略和方法做一综述,重点介绍新的生物技术对药物靶标研究所产生的影响并展望未来发展趋势。     

Using grid techniques for drug target identification

The completion of the sequencing of the human genome has opened an unprecedented opportunity in the discovery of novel drug targets for disease therapy. However, one of the major challenges facing the drug discovery community is the expanding of data and the need of large-scale computational power in a collaborative environment. Grid techniques can present an architectural framework that aims to provide access to heterogeneous resources in a secure, reliable and scalable manner across various administrative boundaries for drug discovery, which has been a promising strategy for solving large-scale problems in modern pharmaceutical R&D. In this review, we discuss the current applications of Grid technology in drug target protein identification process; and an overview of drug target discovery system architecture, focusing in particular on the data manager service system architecture is also proposed.     

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。     

系统生物学——药物研发的新动力

系统生物学是研究生物系统中所有组成成分以及特定条件下这些组分间相互关系的学科。它以干涉生物活动过程及人工模拟为主要手段，以生物信息为基础，是近年提出的新研究领域，其主要特点是对已有生命科学认识的系统整合。系统生物学的理论与方法以及相关的研究结果将为新药研发以及中医药研究提供新的视角与手段，成为药物研究的新动力。     

Discovery of a new method for potent drug development using power function of stoichiometry of homomeric biocomplexes or biological nanomotors

Introduction: Multidrug resistance and the appearance of incurable diseases inspire the quest for potent therapeutics.

Areas covered: We review a new methodology in designing potent drugs by targeting multi-subunit homomeric biological motors, machines or complexes with Z > 1 and K = 1, where Z is the stoichiometry of the target, and K is the number of drugged subunits required to block the function of the complex. The condition is similar to a series electrical circuit of Christmas decorations: failure of one light bulb causes the entire lighting system to lose power. In most multi-subunit, homomeric biological systems, a sequential coordination or cooperative action mechanism is utilized, thus K equals 1. Drug inhibition depends on the ratio of drugged to non-drugged complexes. When K = 1, and Z > 1, the inhibition effect follows a power law with respect to Z, leading to enhanced drug potency. The hypothesis that the potency of drug inhibition depends on the stoichiometry of the targeted biological complexes was recently quantified by Yang-Hui’s Triangle (or binomial distribution), and proved using a highly sensitive in vitro phi29 viral DNA packaging system. Examples of targeting homomeric bio-complexes with high stoichiometry for potent drug discovery are discussed.

Expert opinion: Biomotors with multiple subunits are widespread in viruses, bacteria and cells, making this approach generally applicable in the development of inhibition drugs with high efficiency.     

Using reverse docking for target identification and its applications for drug discovery

ABSTRACT

Introduction: In contrast to traditional molecular docking, inverse or reverse docking is used for identifying receptors for a given ligand among a large number of receptors. Reverse docking can be used to discover new targets for existing drugs and natural compounds, explain polypharmacology and the molecular mechanism of a substance, find alternative indications of drugs through drug repositioning, and detecting adverse drug reactions and drug toxicity.

Areas covered: In this review, the authors examine how reverse docking methods have evolved over the past fifteen years and how they have been used for target identification and related applications for drug discovery. They discuss various aspects of target databases, reverse docking tools and servers.

Expert opinion: There are several issues related to reverse docking methods such as target structure dataset construction, computational efficiency, how to include receptor flexibility, and most importantly, how to properly normalize the docking scores. In order for reverse docking to become a truly useful tool for the drug discovery, these issues need to be adequately resolved.     

药物靶点的发展前景及需要解决的关键问题

[摘要]随着人类基因组计划的完成、基因功能的发现,以及各种高通量筛选方法的实现,药物靶点已经成为了现代创新药物研发的一个重要环节。但进入临床试验和上市的新药数量并未随着潜在靶点的增加而有所增长,甚至还出现了下降趋势。文中分析了目前创新药物数量减少的原因,阐明了科学技术发展进程对药物靶点的影响,在此基础上预测了药物靶点的发展前景;同时,也对药物靶点领域需解决的关键问题进行了探讨。     

Hierarchical pulmonary target nanoparticles via inhaled administration for anticancer drug delivery

Inhalation administration, compared with intravenous administration, significantly enhances chemotherapeutic drug exposure to the lung tissue and may increase the therapeutic effect for pulmonary anticancer. However, further identification of cancer cells after lung deposition of inhaled drugs is necessary to avoid side effects on normal lung tissue and to maximize drug efficacy. Moreover, as the action site of the major drug was intracellular organelles, drug target to the specific organelle is the final key for accurate drug delivery. Here, we designed a novel multifunctional nanoparticles (MNPs) for pulmonary antitumor and the material was well-designed for hierarchical target involved lung tissue target, cancer cell target, and mitochondrial target. The biodistribution in vivo determined by UHPLC–MS/MS method was employed to verify the drug concentration overwhelmingly increasing in lung tissue through inhaled administration compared with intravenous administration. Cellular uptake assay using A549 cells proved the efficient receptor-mediated cell endocytosis. Confocal laser scanning microscopy observation showed the location of MNPs in cells was mitochondria. All results confirmed the intelligent material can progressively play hierarchical target functions, which could induce more cell apoptosis related to mitochondrial damage. It provides a smart and efficient nanocarrier platform for hierarchical targeting of pulmonary anticancer drug. So far, this kind of material for pulmonary mitochondrial-target has not been seen in other reports.