Mega-Trends in Drug Discovery and Development

Abstract

Ten “mega-trends” influencing the nature of modern pharmaceutical research extending to the turn of the century are illustrated. Presented are the projected changes relating to drug development strategies, costs and time perspectives, the structure of the industry, the emerging importance of biotechnology, immunopharmacology, drug delivery systems and the early diagnosis of disease. the environmental and socio-economic impact of these trends on society are assessed as they relate to the broader concern for more effective and efficient health care.     

系统生物学与药物发现研究

系统生物学是假说驱动的科学，是21世纪医学与生物学的核心驱动力。近代药物发现研究主要基于药物新靶点的发现，但是在疾病生物学模型中，化合物的有效性与安全性并不全决定于靶点的选择，系统生物学为药物发现提供了一个全新的研究模式，能明显降低新药研究开发的时间与费用。     

New Advances in Drug Discovery

The conference covered the most exciting recent advances in industry and academia in areas related to drug discovery and development. Topics included candidates currently in clinical development, new technologies aimed at facilitating the drug discovery process and potential new targets. Targets in clinical development included inhibitors of lipoprotein-associated phospholipase A₂ for atherosclerosis, IL-1β converting enzyme inhibitors for inflammatory disorders and a novel proteasome inhibitor for cancer therapy. New technologies covered a novel system for screening ion channel function, various applications for RNA interference, different imaging modalities, as well as mRNA microarrays to facilitate toxicological assessment. New targets included the ATP-binding cassette family of transporters and the recently elucidated sulfation pathways.     

Psychiatric Drug Discovery and Development

This new conference on Psychiatric Drug Research was organised by the Strategic Research Institute and was chaired by P McGonigle (Wyeth Research, USA) and D Schoepp (Eli Lilly, USA). The 2-day meeting featured presentations from an international assembly of industrial and academic experts who have significantly contributed to the current body of knowledge in the field of psychotherapeutics. D Weinberger (NIMH, USA) gave an elegant keynote lecture on the application of genomics in psychopharmacology. Other presentations covered the latest technological advances, animal models and mechanistic approaches utilised in drug discovery for neuropsychiatric disorders and reviewed the current status of numerous novel targets resulting from these strategies.     

The Evolving Role of Drug Metabolism in Drug Discovery and Development

Drug metabolism in pharmaceutical research has traditionally focused on the well-defined aspects of absorption, distribution, metabolism and excretion, commonly-referred to ADME properties of a compound, particularly in the areas of metabolite identification, identification of drug metabolizing enzymes (DMEs) and associated metabolic pathways, and reaction mechanisms. This traditional emphasis was in part due to the limited scope of understanding and the unavailability of in vitro and in vivo tools with which to evaluate more complex properties and processes. However, advances over the past decade in separate but related fields such as pharmacogenetics, pharmacogenomics and drug transporters, have dramatically shifted the drug metabolism paradigm. For example, knowledge of the genetics and genomics of DMEs allows us to better understand and predict enzyme regulation and its effects on exogenous (pharmacokinetics) and endogenous pathways as well as biochemical processes (pharmacology). Advances in the transporter area have provided unprecedented insights into the role of transporter proteins in absorption, distribution, metabolism and excretion of drugs and their consequences with respect to clinical drug–drug and drug–endogenous substance interactions, toxicity and interindividual variability in pharmacokinetics. It is therefore essential that individuals involved in modern pharmaceutical research embrace a fully integrated approach and understanding of drug metabolism as is currently practiced. The intent of this review is to reexamine drug metabolism with respect to the traditional as well as current practices, with particular emphasis on the critical aspects of integrating chemistry and biology in the interpretation and application of metabolism data in pharmaceutical research.     

计算机辅助金属酶靶向药物发现的研究进展

金属酶是指含功能必需和(或)结构必需金属离子的酶的统称,广泛参与关键生理和病理过程,是非常重要的药物作用靶标群。金属结合位点的电子和几何结构具有复杂性、多变性和动态性等特点,使得计算机辅助药物设计存在挑战性。本文综述金属结合药效团,基于结构的药物设计,人工智能等策略应用于金属酶靶向药物发现的研究进展、优势和面临挑战,期望能为金属酶靶向创新药物研发提供借鉴和思考。     

Pharmacogenomics and the Drug Discovery Pipeline

One of the key factors in developing improved medicines lies in understanding the molecular basis of the complex diseases we treat. Investigation of genetic associations with disease utilizing advances in linkage disequilibrium-based whole genome association strategies will provide novel targets for therapy and define relevant pathways contributing to disease pathogenesis. Genetic studies in conjunction with gene expression, proteomic, and metabonomic analyses provide a powerful tool to identify molecular subtypes of disease. Using these molecular data, pharmacogenomics has the potential to impact on the drug discovery and development process at many stages of the pipeline, contributing to both target identification and increased confidence in the therapeutic rationale. This is exemplified by the identified association of 5-lipoxygenase-activating protein (ALOX5AP/FLAP) with increased risk of myocardial infarction, and of the chemokine receptor 5 (CCR5) with HIV infection and therapy. Pharmacogenomics has already been used in oncology to demonstrate that molecular data facilitates assessment of disease heterogeneity, and thus identification of molecular markers of response to drugs such as imatinib mesylate (Gleevec) and trastuzumab (Herceptin).Knowledge of genetic variation in a target allows early assessment of the clinical significance of polymorphism through the appropriate design of preclinical studies and use of relevant animal models. A focussed pharmacogenomic strategy at the preclinical phase of drug development will produce data to inform the pharmacogenomic plan for exploratory and full development of compounds. Opportunities post-approval show the value of large well-characterized data sets for a systematic assessment of the contribution of genetic determinants to adverse drug reactions and efficacy. The availability of genomic samples in large phase IV trials also provides a valuable resource for further understanding the molecular basis of disease heterogeneity, providing data that feeds back into the drug discovery process in target identification and validation for the next generation of improved medicines.     

Anti-Cancer Drug Discovery and Development Summit

The 5th Annual Anti-Cancer Drug Discovery and Development Summit brought together an international group of academic and industry scientists to discuss recent therapeutic developments in the field of oncology. The focus of the meeting was novel targeted approaches, i.e., those agents directed against targets that are overexpressed or overactive in tumour cells. It was acknowledged that cytotoxic agents will continue to play a key role in the treatment of cancer and new developments in this area were also discussed. With over 400 anticancer drugs in clinical development and a number of recent registrations, there is great optimism that significant therapeutic advances can be made.     

药物设计和研发中的定量构动关系研究进展

概述定量构动关系研究的内容和方法。综述定量构动关系研究中对药动学特性的预测,包括对药物吸收、分布、代谢和排泄特征的预测,以及定量构动关系研究对药物设计和研发的指导意义。     

Mass Spectrometry Innovations in Drug Discovery and Development

This review highlights the many roles mass spectrometry plays in the discovery and development of new therapeutics by both the pharmaceutical and the biotechnology industries. Innovations in mass spectrometer source design, improvements to mass accuracy, and implementation of computer-controlled automation have accelerated the purification and characterization of compounds derived from combinatorial libraries, as well as the throughput of pharmacokinetics studies. The use of accelerator mass spectrometry, chemical reaction interface-mass spectrometry and continuous flow-isotope ratio mass spectrometry are promising alternatives for conducting mass balance studies in man. To meet the technical challenges of proteomics, discovery groups in biotechnology companies have led the way to development of instruments with greater sensitivity and mass accuracy (e.g., MALDI-TOF, ESI-Q-TOF, Ion Trap), the miniaturization of separation techniques and ion sources (e.g., capillary HPLC and nanospray), and the utilization of bioinformatics. Affinity-based methods coupled to mass spectrometry are allowing rapid and selective identification of both synthetic and biological molecules. With decreasing instrument cost and size and increasing reliability, mass spectrometers are penetrating both the manufacturing and the quality control arenas. The next generation of technologies to simplify the investigation of the complex fate of novel pharmaceutical entities in vitro and in vivo will be chip-based approaches coupled with mass spectrometry.     

Case Histories in Drug Discovery and Design 2001

The Society for Medicines Research (SMR) held a one-day symposium, entitled "Case Histories in Drug Discovery 2001," on December 6, 2001, at the National Heart and Lung Institute in London. The talks shared one common theme: success stories in drug discovery that have led to new and improved products for therapeutic use. With an emphasis on individual contributions to drug research, each story was considered in the context of an ever-changing, high-risk industry in which research processes are complicated, the success rate is low and costs are extreme. Also incorporated in the meeting was the presentation of the "SMR Award for Drug Discovery," an award given in recognition of outstanding achievement in and contribution to drug discovery. (c) 2002 Prous Science. All rights reserved.     

The Alabama Drug Discovery Alliance: A Collaborative Partnership to Facilitate Academic Drug Discovery

The Alabama Drug Discovery Alliance is a collaboration between the University of Alabama at Birmingham and Southern Research Institute that aims to support the discovery and development of therapeutic molecules that address an unmet medical need. The alliance builds on the expertise present at both institutions and has the dedicated commitment of their respective technology transfer and intellectual property offices to guide any commercial opportunities that may arise from the supported efforts. Although most projects involve high throughput screening, projects at any stage in the drug discovery and development pathway are eligible for support. Irrespective of the target and stage of any project, well-functioning interdisciplinary teams are crucial to a project’s progress. These teams consist of investigators with a wide variety of expertise from both institutions to contribute to the program’s success.     

Toxicogenomics in Drug Discovery and Drug Development: Potential Applications and Future Challenges

Abstract Despite the massive investments made by pharmaceutical companies on drug research and development, the number of new drug approvals has remained stagnant in the past decades. It is well known that developing safe and effective new drugs is a long, difficult, and expensive process. While the cost of developing new drugs is increasing rapidly, withdrawals of drugs from the marketplace due to adverse drug reactions (ADR) and/or toxicity is increasing concurrently. The recent advent of high-throughput in silico (computer softwares) and in vitro (cell cultures) screenings have somewhat alleviated some, but not all, of these challenges by providing an efficient and effective way for developing safer and better drugs. This emerging technology, known as toxicogenomics, has great potential to facilitate the development of methodologies that could predict the long-term toxic effects of compounds using relatively short-term bioassays. This review is aimed at discussing the potential applications and future challenges of toxicogenomics in drug discovery and drug development.