Potential insight for drug discovery from high-fidelity receptor-mediated transduction mechanisms in insects

Introduction: There is a pervasive and growing concern about the small number of new pharmaceutical agents. There are many proposed explanations for this trend that do not involve the drug-discovery process per se, but the discovery process itself has also come under scrutiny. If the current paradigms are indeed not working, where are novel ideas to come from? Perhaps it is time to look to novel sources.

Areas covered: The receptor-signaling and second-messenger transduction processes present in insects are quite similar to those in mammals (involving G proteins, ion channels, etc.). However, a review of these systems reveals an unprecedented degree of high potency and receptor selectivity to an extent greater than that modeled in most current drug-discovery approaches.

Expert opinion: A better understanding of insect receptor pharmacology could stimulate novel theoretical and practical ideas in mammalian pharmacology (drug discovery) and, conversely, the application of pharmacology and medicinal chemistry principles could stimulate novel advances in entomology (safer and more targeted control of pest species).     

Challenges for drug discovery and development in China

Introduction: The drug development industry is restructuring worldwide in terms of the research and development process. As with pharmaceuticals in the west, China faces major challenges for drug discovery and development.

Areas covered: In this review, the authors discuss anti-cancer, anti-allergy, anti-infectious, and proprietary Chinese Medicines (pCM) for various chronic diseases (such as the allergic diseases: eczema, asthma and allergic rhinitis), which remain the contemporary therapeutic strategies that are being explored and developed. Drug transporters, disease specific biomarkers, pharmacophores, bioactive natural products and pharmacogenetics are some aspects of research technologies. Proprietary Chinese medicine remains one of the most popular strategies. There is however the issue of good research documentation of efficacy versus adverse effects. China has a complex healthcare system involving a large patient pool.

Expert opinion: Various factors can impact drug development in China including the concurrent use of both western and Chinese medicines, pharmacogenetic variances, lack of multidisciplinary team impact on disease management and drug safety. China may adopt the current development of big data analysis in other countries such as UK and US to build and centralize a nationwide database for better monitoring and clinical evaluation to provide more efficient care at a lower cost.     

Drug discovery strategies for acute radiation syndrome

Introduction: There are at the minimum two major, quite different approaches to advance drug discovery. The first being the target-based drug discovery (TBDD) approach that is commonly referred to as the molecular approach. The second approach is the phenotype-based drug discovery (PBDD), also known as physiology-based drug discovery or empirical approach.

Area covered: The authors discuss, herein, the need for developing radiation countermeasure agents for various sub-syndromes of acute radiation syndromes (ARS) following TBDD and PBDD approaches. With time and continuous advances in radiation countermeasure drug development research, the expectation is to have multiple radiation countermeasure agents for each sub-syndrome made available to radiation exposed victims.

Expert opinion: The majority of the countermeasures currently being developed for ARS employ the PBDD approach, while the TBDD approach is clearly under-utilized. In the future, an improved drug development strategy might be a ‘hybrid’ strategy that is more reliant on TBDD for the initial drug discovery via large-scale screening of potential candidate agents, while utilizing PBDD for secondary screening of those candidates, followed by tertiary analytics phase in order to pinpoint efficacious candidates that target the specific sub-syndromes of ARS.     

Systems drug discovery: a quantitative,objective approach for safer drug development

We are currently witnessing a dramatic change in the pharmaceutical industry as many companies are downscaling their efforts to discover new drug candidates and are instead turning toward collaboration with academic partners. This trend has been dubbed open innovation. The reason for this change of policy stems from the realization that, in spite of massive investments in their drug development programs in the past 30 years, the number of new drugs reaching the market has remained stable over the same period. We review past and present drug discovery strategies and present a novel more holistic approach that we term Systems Drug Discovery. This approach aims at quantifying the physiological state of organ slice cultures using high content imaging and metabolomics. The characterization in a quantitative manner of healthy, diseased, and drug-treated tissues will allow defining a multiparametric space, within which tissues are healthy. This in turn will allow an objective assessment of the impact of candidate drugs on cells. This quantitative approach should help guide the development of new drugs reducing failure rates in clinical phase.     

Searching for Dual Inhibitors of the MDM2‐p53 and MDMX‐p53 Protein–Protein Interaction by a Scaffold‐Hopping Approach

Two libraries of substituted benzimidazoles were designed using a ‘scaffold‐hopping’ approach based on reported MDM2‐p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM2 X‐ray structure. Benzimidazole libraries were prepared using an efficient solution‐phase approach and screened for inhibition of the MDM2‐p53 and MDMX‐p53 protein–protein interactions. Key examples showed inhibitory activity against both targets.     

GPCR heterodimers: asymmetries in ligand binding and signalling output offer new targets for drug discovery

Dimers of GPCRs have held the imagination of researchers for almost 20 years. However, only recently has their value as potentially novel drug targets been increased significantly, and primarily, in the context of GPCR heterodimers. The view of receptor heterodimers as allosteric machines has transformed the way we understand structural and functional asymmetries inherent in their organization. These asymmetries alter both signalling output and how they might be targeted pharmacologically. The paper in this issue of BJP by Siddiquee and colleagues (2013) highlights our growing understanding of such asymmetries and their implications. They show that heterodimers of the angiotensin II AT1 receptor and the apelin receptor recognize and respond to their respective ligands in distinct ways from the parent receptors expressed alone. Further, they demonstrate asymmetric allosteric effects in the context of the heterodimer that may have significant implications for our understanding of such receptor complexes.

Linked Article

This article is a commentary on the research paper by Siddiquee et al., pp. 1104–1117 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2012.02192.x     

The utilization of spirocyclic scaffolds in novel drug discovery

Introduction: Since the first application of antibiotics to treat bacterial infections, the development and spread of resistance has been a persistent threat. An ever evolving pipeline of next-generation therapeutics is required for modern medicine to remain one step ahead of pathogens.

Areas covered: This review describes recent efforts to develop drugs that interrupt the assimilation of iron by bacteria: a process that is vital to cellular homeostasis and is not currently targeted by antibiotics used in the clinic. This review also covers the mechanisms by which bacteria acquire iron for their environment, and details efforts to intervene in these processes, using small molecule inhibitors that target key steps in these pathways, with a special emphasis on recent advances published during the 2010 – 2012 period.

Expert opinion: For decades, the routes used by bacteria to assimilate iron from host and environmental settings have been the subject of intense study. While numerous investigations have identified inhibitors of these pathways, many have stopped short of translating the in vitro results to in vivo proof of concept experiments. The extension of preliminary findings in this manner will significantly increase the impact of the field.     

药物发现过程中人工智能的应用研究进展

人工智能（AI）和机器学习不仅使药物发现和开发实现了质的飞跃,而且帮助药物开发进程进入现代化。机器学习和深度学习算法已应用于药物发现各个阶段,如先导化合物的筛选、多肽合成及小分子药物的发现、最佳给药剂量的确定、类药化合物的设计和药物不良反应的预测、蛋白质间相互作用的预测、虚拟筛选效率的提高、定量构效关系（QSAR）建模和药物重新定位、理化性质和药物靶标亲和力的预测、化合物的结合预测和体内安全性分析、多靶点配体药物分子的设计以及临床试验的设计。简要综述了AI算法和传统化学相结合以提高药物发现的效率以及AI在药物发现过程中的应用研究进展,以期为AI应用于药物发现提供一定参考。     

Current drug discovery strategies for treatment of hepatitis C virus infection

Objectives Hepatitis C virus (HCV) infection represents a major worldwide‐health problem. The current standard of care is combination therapy with pegylated interferon and ribavirin, which achieves a successful response in only approximately 40% of genotype I patients. Key findings The biology of HCV infection has been under intensive research and important progress has been made in understanding the replication cycle of the virus. Several therapeutic targets have been under investigation, such as NS3 protease, NS4A replicase and NS5B polymerase. New potential targets, such as NS2 protease, as well as CD‐81 and claudin‐1 entry co‐receptors, have also been identified. Summary Clinical evaluations of drug candidates targeting NS3 protease, NS4A cofactor, and NS5B polymerase have demonstrated the potential of developing small molecules that interfere with the replication of the virus. Additional issues, including genotype coverage, resistant mutations, and combination therapy represent major challenges for future drug discovery efforts.     

Glycobiology of the Leishmania parasite and emerging targets for antileishmanial drug discovery

Importance of the field: Parasitic diseases that pose a threat to human life include leishmaniasis – caused by protozoa of Leishmania species. Existing drugs have limitations due to deleterious side effects like teratogenicity and factors like cost and drug resistance, thus furthering the need to develop this area of research.

Areas covered in this review: We came across drug targets, very recently characterised, cloned and validated by genomics and bioinformatics. We bring these promising drug targets into focus so that they can be explored to their fullest.

What the reader will gain: In an effort to bridge the gaps between existing knowledge and future prospects of drug discovery, we found interesting studies validating drug targets and paving the way for better experiments to be designed. In a few cases, novel pathways have been characterized, while in others, well established pathways when probed further, led to the discovery of new drug targets.

Take home message: The review constitutes a comprehensive report on upcoming drug targets, with emphasis on glycosylphosphatidylinositol (GPI)-anchored glycoconjugates along with related biochemistry of enolase, glycosome and purine salvage pathways, as we strive to bring ourselves a step closer to being able to combat this deadly disease.     

Principles and applications of Raman spectroscopy in pharmaceutical drug discovery and development

Introduction: In recent years, Raman spectroscopy has become increasingly important as an analytical technique in various scientific areas of research and development. This is partly due to the technological advancements in Raman instrumentation and partly due to detailed fingerprinting that can be derived from Raman spectra. Its versatility of applications, rapidness of collection and easy analysis have made Raman spectroscopy an attractive analytical tool.

Areas covered: The following review describes Raman spectroscopy and its application within the pharmaceutical industry. The authors explain the theory of Raman scattering and its variations in Raman spectroscopy. The authors also highlight how Raman spectra are interpreted, providing examples.

Expert opinion: Raman spectroscopy has a number of potential applications within drug discovery and development. It can be used to estimate the molecular activity of drugs and to establish a drug’s physicochemical properties such as its partition coefficient. It can also be used in compatibility studies during the drug formulation process. Raman spectroscopy’s immense potential should be further investigated in future.     

Clinical implications from drug–drug and drug–disease interactions in older people

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绿色荧光蛋白在药物发现研究中的应用进展

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药代动力学人体预测及其在新药研发中的应用

药物代谢和药代动力学(DMPK)通过揭示药物的体内代谢处置过程,理解药物药理效应和毒副反应的体内物质基础,是连接药物分子及其性质与生物学效应的桥梁。DMPK人体预测应用模型拟合技术,由人体外试验数据和动物体内外数据预测人体药代动力学性质,并与药效动力学和毒性评价相关联,可提高新药研发效率、降低临床失败率和节省资源。经典的异速放大法和体外-体内外推法主要用于预测人体清除率和稳态表观分布容积等重要的药代动力学参数。近10年来,基于生理的药代动力学模型(PBPK)的快速发展和应用实践,推动了DMPK人体预测在新药研发、药物监管、临床合理和个体化用药中的应用。PBPK模型不仅能预测消除和分布等参数,还能用于药物人体药代动力学行为的预测,包括血药浓度-时间曲线和药物-药物相互作用,以及不同人群体内药代动力学和药代-药效预测。作为新药研发的转化科学技术以及个体化用药的指导工具,DMPK人体预测将具有更为广泛的应用价值。     

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.     

Fragment‐based drug discovery as alternative strategy to the drug development for neglected diseases

Neglected diseases (NDs) affect large populations and almost whole continents, representing 12% of the global health burden. In contrast, the treatment available today is limited and sometimes ineffective. Under this scenery, the Fragment‐Based Drug Discovery emerged as one of the most promising alternatives to the traditional methods of drug development. This method allows achieving new lead compounds with smaller size of fragment libraries. Even with the wide Fragment‐Based Drug Discovery success resulting in new effective therapeutic agents against different diseases, until this moment few studies have been applied this approach for NDs area. In this article, we discuss the basic Fragment‐Based Drug Discovery process, brief successful ideas of general applications and show a landscape of its use in NDs, encouraging the implementation of this strategy as an interesting way to optimize the development of new drugs to NDs.