Targeting the vitamin D receptor: advances in drug discovery

The vitamin D receptor (VDR), a member of the nuclear receptor superfamily, mediates the biological action of 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], the active form of vitamin D. VDR regulates bone and calcium homeostasis, immunity, cellular differentiation and other physiological processes. Mutations in the VDR gene were identified in hereditary vitamin D-resistant rickets (HVDRR), and VDR-null mice exhibit the HVDRR phenotype, characterised by rickets and hypocalcaemia. In addition to the treatment of rickets, vitamin D analogues are important therapeutics in osteoporosis and psoriasis. Vitamin D analogues are effective drugs in experimental models of immune disorders and malignancies, such as breast cancer, prostate cancer and leukaemia. The development of functionally selective VDR-targeted drugs is leading to an enhanced understanding and novel therapies for these VDR-related diseases.     

Recent advances in pharmacophore modeling and its application to anti-influenza drug discovery

Introduction: The emergence of the highly pathogenic avian influenza (HPAI) H5N1 virus and the recent global circulation of H1N1 swine-origin influenza virus in 2009 have highlighted the need for new anti-influenza therapies. This has been made all the more important with the emergence of antiviral-resistant strains. Recent progress in achieving three-dimensional (3D) crystal structures of influenza viral proteins and efficient tools available for pharmacophore-based virtual screening are aiding us in the discovery and design of new antiviral compounds.

Areas covered: This review discusses pharmacophore modeling as a potential cost-effective and time-saving technology for new drug discovery as an alternative to high-throughput screening. Based on this technical platform, the authors discuss current progress and future prospects for developing novel influenza antivirals against pre-existing or emerging novel targets.

Expert opinion: Although it might be at an infant stage of development, the availability of the 3D crystal structures of influenza viral proteins is expected to accelerate the application of structure-based drug design (SBDD) and pharmacophore modeling. Furthermore, the neuraminidase inhibitor, one of the most successful examples of a SBDD, still receives great attention because of its superb antiviral activities and the resistance of influenza strains to oseltamivir. However, despite much success, pharmacophore-based virtual screening exhibits limited predictive power in hit identification. Further improvements in pharmacophore detection algorithms, proper combinations of in silico methods as well as judicious choosing of compounds are expected to improve the hit rate. With the help of these technologies, the discovery of anti-influenza agents will be accelerated.     

Structure of Class B GPCRs: new horizons for drug discovery

Class B GPCRs of the secretin family are important drug targets in many human diseases including diabetes, neurodegeneration, cardiovascular disease and psychiatric disorders. X-ray crystal structures for the glucagon receptor and corticotropin-releasing factor receptor 1 have now been published. In this review, we analyse the new structures and how they compare with each other and with Class A and F receptors. We also consider the differences in druggability and possible similarity in the activation mechanisms. Finally, we discuss the potential for the design of small-molecule modulators for these important targets in drug discovery. This new structural insight allows, for the first time, structure-based drug design methods to be applied to Class B GPCRs.     

G蛋白偶联受体二聚化在药物开发中所发挥的特异性作用(英文)

G蛋白偶联受体(GPCRs)是与G蛋白相偶联的七次跨膜受体,其成员有上千种,是重要的药物靶点之一。目前,GPCRs相关药物占市场上药物的40%-50%。在过去的十年中,对GPCRs主要以单体的形式存在着的这一假说做出了重新评估,大量事实证明GPCRs也能以同源或异源二聚体,甚至是高阶寡聚体的形式存在,比较热门的领域是GPCRs二聚化。最近研究表明同源或异源二聚化有不同于单体的特异功能特征,包括配体识别、信号转导、运输等。同时,在较少副作用治疗疾病的新药开发上,具有不同病理和信号转导途径的二聚体的出现开辟了新的领域。本综述主要介绍二聚体的特异结构及其特异的信号转导途径,从而有助于在GPCRs药物开发中取得丰硕的成果。     

The use of constitutively active GPCRs in drug discovery and functional genomics

The complete sequencing of the human genome has afforded researchers the opportunity to identify novel G-protein-coupled receptors (GPCRs) that are expressed in human tissues. The successful identification of hundreds of GPCRs represents the single greatest opportunity for novel drug development today. However, the lack of identified ligands for these GPCRs has limited their utility for traditional drug discovery approaches that focus on ligand-based assay methods to discover and pharmacologically characterize drug candidates. Here, we review the use of constitutively activated GPCRs in the discovery pathway, both as a means to overcome the limitations of traditional drug discovery at novel GPCRs and as a tool to investigate the functionality of these receptors.     

3D models of neurodegeneration: implementation in drug discovery

A lack of in vitro models that robustly represent the complex cellular pathologies underlying neurodegeneration has resulted in a translational gap between in vitro and in vivo results, creating a bottleneck in the development of new therapeutics. In the past decade, new and complex 3D models of the brain have been published at an exponential rate. However, many novel 3D models of neurodegeneration overlook the validation and throughput requirements for implementation in drug discovery. This therefore represents a knowledge gap that could hinder the translation of these models to drug discovery efforts. We review the recent progress in the development of 3D models of neurodegeneration, examining model design benefits and validation techniques, and discuss opportunities and standards for 3D models of neurodegeneration to be implemented in drug discovery and development.     

Peptide-based drug discovery: Current status and recent advances

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3D in vitro technology for drug discovery

Three-dimensional (3D) in vitro systems that can mimic organ and tissue structure and function in vivo, will be of great benefit for a variety of biological applications from basic biology to toxicity testing and drug discovery. There have been several attempts to generate 3D tissue models but most of these models require costly equipment, and the most serious disadvantage in them is that they are too far from the mature human organs in vivo. Because of these problems, research and development in drug discovery, toxicity testing and biotech industries are highly expensive, and involve sacrifice of countless animals and it takes several years to bring a single drug/product to the market or to find the toxicity or otherwise of chemical entities. Our group has been actively working on several alternative models by merging biomaterials science, nanotechnology and biological principles to generate 3D in vitro living organs, to be called "Human Organs-on-Chip", to mimic natural organ/tissues, in order to reduce animal testing and clinical trials. We have fabricated a novel type of mechanically and biologically bio-mimicking collagen-based hydrogel that would provide for interconnected mini-wells in which 3D cell/organ culture of human samples in a manner similar to human organs with extracellular matrix (ECM) molecules would be possible. These products mimic the physical, chemical, and biological properties of natural organs and tissues at different scales. This paper will review the outcome of our several experiments so far in this direction and the future perspectives.     

Fragment-based approach to drug lead discovery: overview and advances in various techniques

In the last 20 years the advent of new technologies, such as high-throughput screening (HTS) and combinatorial chemistry, has produced new tools for the discovery of biologically active molecules. In the past decade, fragment-based drug discovery has emerged as a more rational and focused approach that concentrates on the quality, rather than the quantity, of hits and leads. The principles behind this strategy are different from those that represented the basis of conventional HTS. The starting point of this approach is always a small chemical entity (typically MW 150-200), a fragment, with low affinity for the selected target. Fragments should satisfy key features such as diversity, reduced structural complexity, aqueous solubility and availability. Because of their small size, they occupy a smaller region of chemical space if compared with classical HTS compounds; hence, fragment libraries provide a good diversity with a relatively low number of compounds. Classical biochemical assays are often not suitable to detect the low binding affinities involved, so some well known biophysical techniques, such as nuclear magnetic resonance and x-ray, have been opportunely modified in order to render them able to perform the task. When selecting fragments suitable for subsequent optimization, a useful parameter has been introduced, the ligand efficiency, which is defined as the free energy of binding divided by the non-hydrogen atom count. Once selected, a fragment must undergo a heavy elaboration to improve binding affinity, at the same time acquiring drug-like properties. There are two main ways to go on at this point. The most common one is the so-called 'fragment evolution', consisting of a stepwise and systematic addition of chemical functionalities to the starting fragment core, together with a continuous feedback for pharmacological and physicochemical properties. The second one, less common but with great potential, is 'fragment linking': when two or more fragment hits are found to bind in adjacent regions of the target protein, they can be linked through appropriate spacers to rapidly produce a single molecule with much higher binding affinity. Two representative case histories are described: Abbott's ABT 518, an MMP (matrix metalloproteinase) inhibitor, and Eli-Lilly's LY-517717, an inhibitor of factor Xa serine protease. In addition, a list of molecules claimed to be derived from fragment approach and currently undergoing clinical trials is presented.     

Conquering influenza: recent advances in anti-influenza drug discovery

Morbidity and mortality associated with influenza virus infection have cut a wide swathe through medical history. Even with the development of killed virus vaccines, illness due to influenza virus infection continues to be a major health problem throughout the world. This may change over the next few years with the development of a new class of antiviral agents targeting the catalytic site of the viral neuraminidase enzyme. These agents have been demonstrated to be both efficacious and clinically beneficial. In addition, investigation into alternative anti-influenza targets continues. These include inhibitors of hemagglutinin-mediated functions, the viral polymerase and new inhibitors of M2 ion channel activity.     

多组分反应及其在新药研究中的应用

本文对多组分反应的发展进行了回顾，简述了其在结构多样性和复杂性的化合物和化合物库合成上的优势，以及在新药研究中新先导物的发现和结构优化上的重要应用价值，简要介绍了几种重要的多组分反应和探索新多组分反应的方法。     

RNAi-based drug discovery and its application to therapeutics

The discovery of RNA interference (RNAi) for target-specific gene silencing via short interfering RNA (siRNA) has rapidly created a powerful tool for the exploration of pathogenesis of disease. The identification of this remarkable molecular pathway has manifested in the new field of RNAi therapy. In efforts to establish the therapeutic application of RNAi therapy, a major focus has been on target gene-specific siRNA-delivery technology in vivo. In particular, creating a pinpoint delivery system for siRNAs is a priority because such a system would be a key technology for the development of the next generation of drugs, including anticancer therapies. Drug discovery studies and novel treatments based on RNAi are currently targeting a wide range of diseases, including viral infections and cancer. This feature review focuses on recent progress in the nonviral systemic delivery of siRNA in animal models and in clinical trials, as well as on the application of microRNAs in RNAi therapy.     

BacMam technology and its application to drug discovery

The recombinant baculovirus/insect cell system was firmly established as a leading method for recombinant protein production when a new potential use for these viruses was revealed in 1995. It was reported that engineered recombinant baculoviruses could deliver functional expression cassettes to mammalian cell types; a system which has come to be known as BacMam gene delivery. In the field of high-throughput screening the failure of many common transient gene delivery methods in reproducibility and cell survival has caused investigators to routinely apply stable cell lines in support of cell-based assays. The ease of use, versatility, safety and economics of the BacMam system makes transient gene delivery a viable option in the high-throughput screening setting and in most instances circumvents many of the limitations of stable cell lines. Although a few pharmaceutical companies have embraced the technology, its use is poised to become more widespread with increased familiarity and the emergence of enabling products based on the BacMam system.     

Developments with 3D bioprinting for novel drug discovery

ABSTRACT

Introduction: Although there have been significant contributions from the pharmaceutical industry to clinical practice, several diseases remain unconquered, with the discovery of new drugs remaining a paramount objective. The actual process of drug discovery involves many steps including pre-clinical and clinical testing, which are highly time- and resource-consuming, driving researchers to improve the process efficiency. The shift of modelling technology from two-dimensions (2D) to three-dimensions (3D) is one of such advancements. 3D Models allow for close mimicry of cellular interactions and tissue microenvironments thereby improving the accuracy of results. The advent of bioprinting for fabrication of tissues has shown potential to improve 3D culture models.

Areas covered: The present review provides a comprehensive update on a wide range of bioprinted tissue models and appraise them for their potential use in drug discovery research.

Expert opinion: Efficiency, reproducibility, and standardization are some impediments of the bioprinted models. Vascularization of the constructs has to be addressed in the near future. While much progress has already been made with several seminal works, the next milestone will be the commercialization of these models after due regulatory approval.     

Target-drug interactions: first principles and their application to drug discovery

In this review, we begin by introducing the basic principles of kinetics and thermodynamics of target-drug binding within the context of drug discovery. In addition, we present a meta-analysis of the recent literature describing the kinetic and thermodynamic resolution of successful clinical candidates with diverse mechanisms of action. We finish by discussing the best practices in the triage and chemical optimization towards clinical candidates with maximal in vivo efficacy devoid of adverse events.