药物重定位候选药物筛选路径

相对传统新药研发模式,药物重定位策略发现药物新用途具有显著的成本效益优势,能加快药物上市步伐,满足恶性肿瘤、罕见病、个性化医疗等特定领域药物临床用药需求,因而被各界关注。本文主要介绍了药物重定位的一般流程与候选药物筛选路径,如从非理性设计方法向基于相似性、基于结构虚拟筛选、推理与机器学习等理性设计方法发现重定位药物的系统性转变。     

基于机器学习和大数据挖掘的药物重定位算法综述

药物重定位(又称药物重使用或药物重配置)是将现有治疗方法应用于新的疾病的过程的一种药物研发方法。新药研发成本高、失败率高,使得对现有药物进行重新定位成为目前研究的热点。在高通量测序技术的帮助下,许多有效的算法被提出并应用于药物的重新定位。目前用于药物和化合物重定位的算法可分为基于特征的方法、基于矩阵分解的方法、基于网络的方法3大类。分别对这3类常用方法进行综述,总结这些方法的优缺点,并对未来药物重新定位方法的发展方向进行剖析,以期达到帮助我国科研工作者开发更加有效的药物重定位算法,增加我国社会经济效益的目的。     

老药新用研究策略与应用(2)——基于新适应证发现的研究策略与应用

近年来，“老药新用”概念被用于许多临床上正用于治疗疾病的药物，以及曾经或正处于临床前或临床试验中的候选药物。历史上及当前一系列著名的药物重定位应用，推动了基于“老药新用”的药物研发，并使之应用于新的适应证。该文基于新适应证的发现，论述新药研究中药物重定位，讨论了一系列新适应证的“老药新用”的科学研究基础及关键研究策略，包括根据药物现有基本作用机制发现新适应证，根据药物副作用发现新适应证，以及基于药物新作用机制发现新适应证等。     

蛋白质组学技术在网络药理学中的应用

蛋白质组学发展至今已日趋成熟,在生物医药相关领域研究中的应用显著增加,与之相关的样品制备技术、蛋白定量方法及先进的质谱仪器也得到了快速发展。网络药理学是近年来提出的新药发现新策略,是药理学的新兴分支学科,它从整体的角度探索药物与疾病的关联性,发现药物靶标,指导新药研发。将蛋白质组学技术应用于网络药理学研究用,加速药物靶点的确认,从而设计多靶点药物或药物组合。综述了蛋白质组学技术的新近研究进展,并简单概述了其在网络药理学中的应用。     

网络药理学:药物发现的新思想

新药研发是医药产业发展的核心驱动力,也是社会发展的重要需求,但近年来,随着对药物研发要求的不断提高,新药研发正面临着巨大困难,单靶点高选择性的新药研发思想遇到了挑战,已经显示出发展的局限性。网络药理学是近年来在单靶点药物研究的基础上提出的新药发现新策略。本文围绕网络药理学的形成基础和目前研究现状,探讨网络药理学发展的方向和应用前景,同时分析网络药理学的局限性和存在的问题,并通过与传统中医药学理论和中药复方有效成分组学的思想相比较,探讨网络药理学在新药研发中的应用。     

新药发现阶段类药性评选

类药性对药物体外体内药理学有重要影响。类药性评选成为国外新药发现研究战略的新组分。类药性数据有助于分析新药研发阶段化合物的性质，指导优先选择和优化结构。本文综述了类药性研究范畴、体外体内高通量测量方法及它对新药发现的指导作用。     

来源于经典名方的中药新药高质量发展战略思考

目前中药新药开发及审批遇到了瓶颈,大部分企业研发的积极性不高,投入不足,尽管有国家重大新药专项的强力拉动,结果并不理想,影响因素是多方面的,其中高品质的创新药物研发不足是其主要的问题之一。慢病己成为影响我国国民健康的主要因素,占全国医疗资源2/3以上,单一靶点药物在慢病的治疗中受到极大的挑战,国际主流学术期刊多篇学术论文讨论了基于系统生物学、生物学信息学、网络药理学等技术针对慢性疾病、复杂性疾病开展多靶点创新是药物的研发将成为未来发展的一条重要途径。Nature刊文指出:多靶点药物开发有望治疗复杂性疾病。中药多成分、多靶点的作用特点有望成为治疗慢性疾病、复杂性疾病的重要选择。中药创新药开发陷入瓶颈期,其中重要的是问题之一有效性证据不足,基础研究薄弱,临床前药效评价研究不足,临床循证证据偏个案,群体循证证据不足,目前研究与评价方法仍不能适合中药的特点,无法真正的发现中药在治疗疾病的优势所在。中药的应用是在中医长期的临床经验的基础上形成的。基于临床大数据创新中药的发现与研发将成为未来中药创新药物研发的重要选择。经典名方、临床经方积累了丰富的经验与价值。如何利用现代生命科学的前沿技术建立符合中药特点的发现与评价方法将成为关键环节。     

网络药理学:认识药物及发现药物的新理念

网络药理学是指将药物作用网络与生物网络整合在一起,分析药物在此网络中与特定节点或模块的相互作用关系,从而理解药物和机体相互作用的科学。网络药理学突破传统的"一个药物一个靶标,一种疾病"理念,代表了现代生物医药研究的哲学理念与研究模式的转变。以系统生物学和网络生物学基本理论为基础的网络药理学具有整体性、系统性的特点,注重网络平衡(或鲁棒性)和网络扰动,强调理解某个单一生物分子(如基因、mRNA或蛋白等)在生物体系中的生物学地位和动力学过程要比理解其具体生物功能更为重要,揭示药物作用的生物学和动力学谱要比揭示其作用的单个靶标或几个"碎片化"靶标更重要,对认识药物和发现药物的理念产生了深远影响。     

压力性损伤治疗药物的研究进展

压力性损伤是临床常见并发症之一,由压力、剪切力和摩擦力与多种内外因素共同作用下以皮肤、肌肉和皮下组织局限性损伤或坏死为特征的损伤。其病因复杂,且易反复发作。目前临床上专用于压力性损伤的药物很少,基于新药临床研究的高失败率,在老药的原适应症以外开发新用途,寻找现有药物的新适应症已成为极具吸引力的新策略,因此,从治疗压力性损伤新适应症药物角度,对其临床相关药物的研究进展进行系统归纳总结,以期为其临床治疗提供参考。     

中国临床药理学发展概况与展望

临床药理学是研究药物与人体之间相互作用及其规律的一门科学,是涉及药理学、医学、药物学、生物学、护理学、毒理学、流行病学、遗传学、数学、统计学、经济学、社会和个体行为学等多学科的交叉学科或综合学科.主要研究内容包括人体(正常,病人)的药动学、药效学和遗传药理学、临床药物评价和Ⅰ、Ⅱ、Ⅲ、Ⅳ期临床试验、治疗药物检测、药物警戒、药物利用、药物流行病学、药物经济学、新药发现与开发等.以往认为临床药理学是药理学的分支学科,还有将药物临床试验等同于临床药理学,均难以涵盖临床药理学的研究内容.临床药理学是指导药物临床合理使用、新药临床安全性有效性评价以及新药发现与开发的科学基础.改革开放以来,中国临床药理学研究经历了知识普及与队伍培育、规范研究与不断提高、蓬勃发展与着力创新三个阶段,在指导临床合理用药、药物临床研究、新药创制、人才培养、国内外学术交流、著作教材和期刊建设以及学术组织建设等方面发挥了重要作用.该文就改革开放以来我国临床药理学发展概况与进展作一简要综述.     

Mining drug-disease relationships : A recommendation system北大核心CSCD

Aim Drug repositioning is to find new indications for existing drugs, however, potential drug-disease relationships are often hidden in millions of unknown relationship. With the analyzing of medical big data, we predict the potential drug-disease relationships. Methods Based on the assumption that similar drugs tend to have similar indications, we applied a recommendation-based strategy to drug repositioning. First, we collected the information of known drug-disease therapeutic effect, side effect, drug characters and disease characters; second, we calculated the drug-drag similarity measurements and disease-disease similarity measurements; last, we used a collaborative filtering (CF) method to predict unknown drug-disease relationships based on the known drug-disease relationships by integrating the similarity measurements, and built a ranking list of prediction results. Results The experiments demonstrated that a-mong the TOP 500 of the list, 12. 8% were supported by clinical experiments or review, and 20% were supported by model organism or cell experiments. Conclusion Compared to the classification model and random sampling results, the CF model can effectively reduce the false positives.     

Clinical pharmacology applications in clinical drug development and clinical care: A focus on Saudi Arabia

Drug development, from preclinical to clinical studies, is a lengthy and complex process. There is an increased interest in the Kingdom of Saudi Arabia (KSA) to promote innovation, research and local content including clinical trials (Phase I-IV). Currently, there are over 650 registered clinical trials in Saudi Arabia, and this number is expected to increase. An important part of drug development and clinical trials is to assure the safe and effective use of drugs. Clinical pharmacology plays a vital role in informed decision making during the drug development stage as it focuses on the effects of drugs in humans. Disciplines such as pharmacokinetics, pharmacodynamics and pharmacogenomics are components of clinical pharmacology. It is a growing discipline with a range of applications in all phases of drug development, including selecting optimal doses for Phase I, II and III studies, evaluating bioequivalence and biosimilar studies and designing clinical studies. Incorporating clinical pharmacology in research as well as in the requirements of regulatory agencies will improve the drug development process and accelerate the pipeline. Clinical pharmacology is also applied in direct patient care with the goal of personalizing treatment. Tools such as therapeutic drug monitoring, pharmacogenomics and model informed precision dosing are used to optimize dosing for patients at an individual level. In KSA, the science of clinical pharmacology is underutilized and we believe it is important to raise awareness and educate the scientific community and healthcare professionals in terms of its applications and potential. In this review paper, we provide an overview on the use and applications of clinical pharmacology in both drug development and clinical care.     

Resolution of controversies in drug/receptor interactions by protein structure. Limitations and pharmacological solutions

Structural biology offers breakthroughs for key issues in receptors, ion channels and transporters. Unfortunately, while knowledge is growing exponentially about receptors and drug targets, there is also an exponential knowledge of all the variables involved. A key issue for structure-based drug design is if there are distinct outcomes from a single structurally defined site. The ways in which drugs can interact with G-protein-coupled receptors (GPCRs) at the orthosteric site can be multiple, and ligands can also interact with allosteric sites. Receptors may exist as homo- or heterodimers, with the potential for distinct pharmacology, and NC-IUPHAR has proposed stringent criteria for recognition of heterodimers (Pin et al., 2007). Furthermore, some drugs have the capacity for activating different signalling cascades from a single receptor (Urban et al., 2007) indicating unique pharmacology. Thus although specific drugs were the main tool by which receptors were (and still can be, if appropriate precautions are taken) classified, drugs may also have distinct pharmacology at certain receptors depending on their chemical structure, showing drug-specific pharmacology rather than the specific-drug pharmacology which had been used in the past to define (and limit) drug classes. Primary structure is an essential but occasionally treacherous tool for defining receptors because distinct primary structures may evolve to perform similar function. This has immense implications in drug screening, and development - which also entails much testing, and selection, in pathophysiological situations.     

Network analysis of FDA approved drugs and their targets

The global relationship between drugs that are approved for therapeutic use and the human genome is not known. We employed graph-theory methods to analyze the Federal Food and Drug Administration (FDA) approved drugs and their known molecular targets. We used the FDA Approved Drug Products with Therapeutic Equivalence Evaluations 26(th) Edition Electronic Orange Book (EOB) to identify all FDA approved drugs and their active ingredients. We then connected the list of active ingredients extracted from the EOB to those known human protein targets included in the DrugBank database and constructed a bipartite network. We computed network statistics and conducted Gene Ontology analysis on the drug targets and drug categories. We find that drug to drug-target relationship in the bipartite network is scale-free. Several classes of proteins in the human genome appear to be better targets for drugs since they appear to be selectively enriched as drug targets for the currently FDA approved drugs. These initial observations allow for development of an integrated research methodology to identify general principles of the drug discovery process.     

海洋药物及其研发新进展

海洋来源的药物在人类与疾病的长期斗争中发挥了重要的作用,“向海洋要药”在新世纪已成为各国政府的共识、研究人员奋斗的目标。本文对截止2017年底国内外已获批上市的海洋药物进行了归纳总结,并重点介绍了欧美等发达国家和我国已上市小分子药物的药物来源、结构、最新药理作用、临床功效和用途、以及研发历程。此外,介绍了国内外进入各期临床研究阶段的67个候选海洋药物,本文以salinosporamide A和河豚毒素为代表,重点介绍了当前处于临床研究阶段的海洋药物的最新进展。