The importance of synthetic drugs for type 2 diabetes drug discovery

Introduction: Type 2 diabetes mellitus (T2DM) is a major metabolic, multi-causal and heterogeneous disorder which causes significant morbidity and mortality with considerable burden to healthcare resources. The number of deaths due to T2DM highlights the insufficiency of the currently available drugs for controlling the disease and its complications and more needs to be done.

Areas covered: This paper reviews the updated pathobiology of T2DM that should be targeted in drug discovery. Further, the article provides discussion on the mechanism of action, side effects and structure of the currently available synthetic drugs. The authors specifically evaluate two newer classes of anti-diabetic agents: dipeptidyl peptidase IV (DPP-4) and sodium-glucose transporter-2 (SGLT2). They also present information on newer synthetic compounds. The article also highlights the key interactions between synthetic compounds and DPP-4 active site residues for rational drug design.

Expert opinion: Numerous anti-hyperglycaemic drugs are currently available but many are limited by their adverse effects. The identification of the 3D structure of DPP-4 has opened new avenues for design, thus aiming to produce drugs that directly exploit the structural characteristics of this binding site. Further, structural- and ligand-based screening techniques have been developed for designing novel DPP-4 and SGLT2 inhibitors. There has also been progress with the design and development of novel T2DM therapeutics including: PPARα/ dual agonists, Sirtuin 1 activators, glycogen phosphorylase inhibitors and protein tyrosine phosphatase 1B inhibitors. Finding new targets and synthesis methods is still essential but it is becoming accepted that no diabetic therapy is ‘best suited' with each patient responding differently.     

Designing transient binding drugs: a new concept for drug discovery

A multitude of weak, or transient, biological interactions (dissociation constant: K(d)>microM), either working alone or in concert, occur frequently throughout biological systems. We are starting to appreciate their importance in complex biological networks. This realization has important implications to drug discovery as we can question the current paradigm of drug design to find the highest possible binders (drugs) to a given target (receptor). Development of transient drugs, defined by their binding to target, can be based on high-off-rates, multivalent approaches or multiple targets. Now, techniques are available to discover such drug candidates. The greatest problem yet to overcome is probably the mind-set of the individual researcher that weak binders are undesired and therefore of no benefit.     

The importance of chronobiology to drug discovery

Drug discovery scientists, faced with the myriad challenges involved in developing novel therapeutics as medicines, have tended to overlook the question of the most beneficial time to administer the drug. Recent developments in our understanding of circadian biology and the availability of tools to characterise the molecular clock indicate that time and duration of dosing may have profound consequences for the efficacy and safety of new and existing therapeutic agents. Progress in the field also suggests that many key physiological mechanisms are remarkably dependent on the circadian clock. It has also become clear that a number of diseases with important unmet medical need display marked circadian variation in their symptoms and severity. These discoveries now reveal opportunities for new therapeutic strategies to be developed that act by modulation of biological rhythms. These novel therapeutic approaches are likely to be facilitated by the continuing development of chemical probes and synthetic ligands targeted to an increasing number of the key proteins that regulate the molecular clock.     

The importance of HT-ADME in drug discovery

The inaugural meeting of the Boston Society High-Throughput Absorption, Distribution, Metabolism and Excretion (HT-ADME) Conference was held in Cambridge, MA (USA). The theme was 'The Importance of HT-ADME in Drug Discovery' and the organizers of the conference stressed the importance of incorporating audience participation and discussion in the field. The conference hosted 65 attendees and 16 presentations, which was a good size to achieve the goal of active participation while maintaining focus on HT-ADME. The speakers provided broad coverage of HT-ADME within the drug discovery arena, while remembering that the overall goal in drug discovery is identifying potential drug candidates to move forward into development.     

The importance of chronobiology to drug discovery

Drug discovery scientists, faced with the myriad challenges involved in developing novel therapeutics as medicines, have tended to overlook the question of the most beneficial time to administer the drug. Recent developments in our understanding of circadian biology and the availability of tools to characterise the molecular clock indicate that time and duration of dosing may have profound consequences for the efficacy and safety of new and existing therapeutic agents. Progress in the field also suggests that many key physiological mechanisms are remarkably dependent on the circadian clock. It has also become clear that a number of diseases with important unmet medical need display marked circadian variation in their symptoms and severity. These discoveries now reveal opportunities for new therapeutic strategies to be developed that act by modulation of biological rhythms. These novel therapeutic approaches are likely to be facilitated by the continuing development of chemical probes and synthetic ligands targeted to an increasing number of the key proteins that regulate the molecular clock.     

Finding new tricks for old drugs: an efficient route for public-sector drug discovery

With the annotation of the human genome approaching completion, public-sector researchers - spurred in part by various National Institutes of Health Roadmap Initiatives - have become increasingly engaged in drug discovery and development efforts. Although large and diverse chemical libraries of 'drug-like' compounds can be readily screened to yield chemically novel scaffolds, transforming these 'chemical probes' into drugs is a daunting endeavour. A more efficient approach involves screening libraries of approved and off-patent medications; both phenotypic- and molecular target-based screening of 'old drugs' can readily yield compounds that could be immediately used in clinical trials. Using case studies, we describe how this approach has rapidly identified candidate medications suitable for clinical trials in disorders such as progressive multifocal leukoencephalopathy and amyotrophic lateral sclerosis. This approach has also led to the discovery of the molecular targets responsible for serious drug side effects, thereby allowing efficient 'counter-screening' to avoid these side effects.     

The molecular epidemiology of pain: a new discipline for drug discovery

Recent candidate gene studies have identified and replicated the first associations between several common polymorphisms and pain severity in humans. Moreover, human studies in twins suggest high heritability for responses to experimental pain stimuli. Human genome-wide association studies of pain phenotypes might identify novel analgesic targets, help to prioritize research among current targets, and increase the likelihood of success for analgesic candidates emerging from animal studies. However, clinical research in pain has largely focused on small neurophysiology-based studies, so expansion of epidemiological understanding will be essential to the success of genetic or proteomic dissection of complex pain disorders. This Perspective outlines how methods of molecular epidemiology, proved effective in the study of other diseases, can enhance the returns from human genomic studies and expedite the development of new drugs to prevent or treat pain.     

Aging biology: a new frontier for drug discovery

INTRODUCTION: The prevalence of age-related pathologies, such as cardiovascular disease, neurodegenerative disease and diabetes type II, has increased dramatically with the rising average age of populations. Antiaging molecules and appropriate animal models need to be developed to prevent and or delay alterations that occur during aging and are manifested as age-associated illnesses. AREAS COVERED: This review covers the main experimental models used in aging research, from invertebrates up to nonhuman primates. The authors discuss studies of the biochemical pathways involved in dietary restriction, which has been associated with life span extension. The authors also describe the implications of sirtuin 1, insulin growth factor, mTOR (the mammalian target of rapamycin) and AMPK activation, which are well-characterized antiaging pathways. All these pathways are highly conserved from invertebrates to nonhuman primates. Although some invertebrate models are used to study the antiaging properties of drugs, mice models and nonhuman primates are more suitable, as the study of changes in memory loss is critical. The review highlights the conservation of the aging pathways between species. EXPERT OPINION: Further studies on aging should focus on two ways: i) improving animal models, for example, the genetically heterogeneous mice and ii) drug research. It is almost impossible to evaluate clinically the efficacy of antiaging drugs. Moreover, caloric restriction currently constitutes the most effective antiaging pathway. Thus, the strategy is to study drugs for aging-associated diseases, such as diabetes, that also have antiaging effects.     

Aging biology: a new frontier for drug discovery

Introduction: The prevalence of age-related pathologies, such as cardiovascular disease, neurodegenerative disease and diabetes type II, has increased dramatically with the rising average age of populations. Antiaging molecules and appropriate animal models need to be developed to prevent and or delay alterations that occur during aging and are manifested as age-associated illnesses.

Areas covered: This review covers the main experimental models used in aging research, from invertebrates up to nonhuman primates. The authors discuss studies of the biochemical pathways involved in dietary restriction, which has been associated with life span extension. The authors also describe the implications of sirtuin 1, insulin growth factor, mTOR (the mammalian target of rapamycin) and AMPK activation, which are well-characterized antiaging pathways. All these pathways are highly conserved from invertebrates to nonhuman primates. Although some invertebrate models are used to study the antiaging properties of drugs, mice models and nonhuman primates are more suitable, as the study of changes in memory loss is critical. The review highlights the conservation of the aging pathways between species.

Expert opinion: Further studies on aging should focus on two ways: i) improving animal models, for example, the genetically heterogeneous mice and ii) drug research. It is almost impossible to evaluate clinically the efficacy of antiaging drugs. Moreover, caloric restriction currently constitutes the most effective antiaging pathway. Thus, the strategy is to study drugs for aging-associated diseases, such as diabetes, that also have antiaging effects.     

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。     

Candidiasis drug discovery and development: new approaches targeting virulence for discovering and identifying new drugs

Introduction: Targeting pathogenetic mechanisms, rather than essential processes, represents a very attractive alternative for the development of new antibiotics. This may be particularly important in the case of antimycotics, due to the urgent need for novel antifungal drugs and the paucity of selective fungal targets. The opportunistic pathogenic fungus Candida albicans is the main etiological agent of candidiasis, the most common human fungal infection. These infections carry unacceptably high mortality rates, a clear reflection of the many shortcomings of current antifungal therapy, including the limited armamentarium of antifungal agents, their toxicity and the emergence of resistance. Moreover, the antifungal pipeline is mostly dry.

Areas covered: This review covers some of the most recent progress toward understanding C. albicans pathogenetic processes and how to harness this information for the development of anti-virulence agents. The two principal areas covered are filamentation and biofilm formation, as C. albicans pathogenicity is intimately linked to its ability to undergo morphogenetic conversions between yeast and filamentous morphologies and to its ability to form biofilms.

Expert opinion: Filamentation and biofilm formation represent high value targets, yet are clinically unexploited, for the development of novel anti-virulence approaches against candidiasis. Although this has proved a difficult task despite increasing understanding at the molecular level of C. albicans virulence, there are some opportunities and prospects for antifungal drug development targeting these two important biological processes.     

Systems Biology: a new hope for drug discovery?

The rapid expansion of biomedical information following the mapping of the human genome has contributed to significant advances in acquiring a highly detailed picture of disease mechanisms at the molecular level. This revolution in biomedical science has also generated hope and expectation for the delivery of novel treatments for serious illnesses. However, the reality is that despite this detailed information the return in terms of delivery of new medicines has been relatively modest.     

Adrenomedullin: a new and promising target for drug discovery

Adrenomedullin (AM) is a 52 amino acid peptide that plays a critical role in several diseases such as hypertension, cancer, diabetes, cardiovascular and renal disorders, among others. Interestingly, AM behaves as a protective agent against some pathologies, yet is a stimulating factor for other disorders. Thus, AM can be considered as a new and promising target for the design of non-peptidic modulators that could be useful for the treatment of those pathologies, by regulating AM levels or the activity of AM. A full decade on from its discovery, much more is known about AM molecular biology and pharmacology, but this knowledge still needs to be applied to the development of clinically useful drugs.     

Bioterrorism: a new frontier for drug discovery and development

Only a few years ago bioterrorism was considered a remote concern but today it has reached the forefront of the public imagination following recent terrorist attacks around the world. The disaster of September 11 2001, followed by anthrax letters sent via the US postal system, and now the renewed tension in the Middle East, have all brought the possibility of bioterrorism a little closer to reality. A number of biological agents could be used in a terrorist attack, including anthrax, botulinum, plague, smallpox, staphylococcal and streptococcal toxins, and the list of emerging pathogens is evolving rapidly. The serious diseases that these agents produce could cause considerable morbidity and mortality if used in a terrorist attack. This evolving threat presents the medical, public health and scientific communities with pressing challenges. The present research efforts in academia are primarily focused on the basic research on the pathogens that are considered to be bioweapons for terrorist attack. Thus, collaborative efforts between academic institutes, pharmaceutical industries and governmental agencies are warranted to translate basic research into drugs, vaccines and diagnostic tests. This review provides a brief overview of the threat from biological weapons and the current biodefense strategy to prevent and control outbreaks of diseases caused by intentional release of these bioweapons of mass destruction.     

Epigenetic protein families: a new frontier for drug discovery

Epigenetic regulation of gene expression is a dynamic and reversible process that establishes normal cellular phenotypes but also contributes to human diseases. At the molecular level, epigenetic regulation involves hierarchical covalent modification of DNA and the proteins that package DNA, such as histones. Here, we review the key protein families that mediate epigenetic signalling through the acetylation and methylation of histones, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones. These protein families are emerging as druggable classes of enzymes and druggable classes of protein-protein interaction domains. In this article, we discuss the known links with disease, basic molecular mechanisms of action and recent progress in the pharmacological modulation of each class of proteins.     

Adrenomedullin: a new and promising target for drug discovery

Adrenomedullin (AM) is a 52 amino acid peptide that plays a critical role in several diseases such as hypertension, cancer, diabetes, cardiovascular and renal disorders, among others. Interestingly, AM behaves as a protective agent against some pathologies, yet is a stimulating factor for other disorders. Thus, AM can be considered as a new and promising target for the design of non-peptidic modulators that could be useful for the treatment of those pathologies, by regulating AM levels or the activity of AM. A full decade on from its discovery, much more is known about AM molecular biology and pharmacology, but this knowledge still needs to be applied to the development of clinically useful drugs.