Current Drug Discovery Research Articles

High-throughput synthesis of azide libraries suitable for direct “click” chemistry and in situ screening

A key challenge in current drug discovery is the development of high-throughput (HT) amenable chemical reactions that allow rapid synthesis of diverse chemical libraries of enzyme inhibitors. The Cu(I)-catalyzed, 1,3-dipolar cycloaddition between an azide and an alkyne, better known as "click chemistry", is one such method that has received the most attention in recent years. Despite its popularity, there is still a lack of robust and efficient chemical strategies that give access to diverse libraries of azide-containing building blocks (key components in click chemistry). We report herein a highly robust and efficient strategy for high-throughput synthesis of a 325-member azide library. The method is highlighted by its simplicity and product purity. The utility of the library is demonstrated with the subsequent "click" synthesis of the corresponding bidentate inhibitors against PTP1B.

製薬企業におけるトランスレーショナルリサーチの役割 ―パラダイムシフトによる医薬品研究開発の生産性向上を目指して―

Current drug discovery, clinical development, and approval process is long, expensive, and inefficient. Less than 1 in 10 promising drug candidates entering phase I clinical trials eventually receive regulatory approval. This is an alarming statistic for the pharmaceutical industry, and the traditional drug development paradigm is no longer sustainable in the face of high attrition risk and increasing development cost. The core problem is lack of innovation in developing effective new therapies for unmet medical needs. There is an urgent need to improve productivity in pharmaceutical research & development (R & D) by closing the gap between bench and bedside and making much earlier and more accurate go/no-go decisions. A paradigm shift that will reinvent the process of R & D is emerging in the pharmaceutical industry. It is time for pharmaceutical companies to introduce new innovative thinking into current drug development strategies.Translational research in the pharmaceutical industry is intended to facilitate the transition of new ideas in basic science to patient cure through improvement of R & D productivity. Exploratory clinical trials, targeted medicine, and biomarkers are major tools for translational research. Simple introduction of new technologies and sciences into the current system/organization is not sufficient. We must change the current paradigm (business model) and, more importantly, our way of thinking (mindset). In this article, the potential roles of translational research in pharmaceutical R & D are discussed, focusing on early drug development (from discovery to proof of concept).

Where is the hope for drug discovery? Let history tell the future

For drug discovery, historical experience is always of significance. Through examining the history of traditional medicines, we find that these medicines have more implications for drug discovery than just providing new chemical entities. The history of traditional medicines indicates that they depended more on the combination of natural agents than on screening new agents to find new remedies. This phenomenon suggests that shifting the current drug discovery paradigm from 'finding new-entity drugs' to 'combining existing agents' may be helpful for overcoming the 'more investment, fewer drugs' challenge. We show that clues to finding antidementia combinatorial drugs can be derived from traditional medicine formulae. It seems that to create a brighter future of drug discovery, we would better go back to history.

Current Applications of Liquid Chromatography/Mass Spectrometry in Pharmaceutical Discovery After a Decade of Innovation

Current drug discovery involves a highly iterative process pertaining to three core disciplines: biology, chemistry, and drug disposition. For most pharmaceutical companies the path to a drug candidate comprises similar stages: target identification, biological screening, lead generation, lead optimization, and candidate selection. Over the past decade, the overall efficiency of drug discovery has been greatly improved by a single instrumental technique, liquid chromatography/mass spectrometry (LC/MS). Transformed by the commercial introduction of the atmospheric pressure ionization interface in the mid-1990s, LC/MS has expanded into almost every area of drug discovery. In many cases, drug discovery workflow has been changed owing to vastly improved efficiency. This review examines recent trends for these three core disciplines and presents seminal examples where LC/MS has altered the current approach to drug discovery.

An orphan GPCR finds a home in the heart

G PROTEIN-COUPLED RECEPTORS (GPCRs) are the largest and most successful targets for pharmacotherapy to date, particularly in the area of cardiovascular disease. These receptors are at the forefront of current drug discovery efforts (7). GPCRs also form the largest family of transmembrane receptors, with nearly 800 GPCR loci (12, 18), of which several hundred are categorized as orphan GPCRs. These orphan receptors have no known endogenous ligand. While it is estimated that 300 or so of these genes are olfactory or chemosensory receptors, 100 or more GPCR orphans remain that may have putative hormonal or neurotransmitter-related functions (3) providing novel targets for disease. Thus, orphans have attracted significant attention in recent years to determine their expression profiles and roles, if any, in physiology and disease. Orphan GPCR research has progressed rapidly in recent years. Originally, researchers used reverse pharmacology by using orphan GPCRs as “hooks” in screening to fish out novel hormone, peptide, and neurotransmitter ligands. This approach has identified novel neuropeptides that regulate feeding, satiety, circadian rhythms, and sleep (3, 17). More recently, large compound libraries have been used to identify chemicals that interact with orphan GPCRs that may have therapeutic potential (4). In all, these efforts have “deorphanized” more than 40 GPCRs, and many of these targets are the focus of ongoing drug development efforts in academia and industry (3, 7).

A reporter assay for target validation in primary neuronal cultures

The deposition of beta-amyloid peptides (Aβ42 and Aβ40) in neuritic plaques is one of the hallmarks of Alzheimer's disease (AD), and genes modulating their brain levels and neuronal effects could result in future disease modifying therapies. The causal association of candidate targets with AD is of paramount importance in current drug discovery, as a lack of efficacy of many candidate drugs is often due to inadequate validation of their pharmacological target. In Alzheimer's as well as in other neurodegenerative diseases, in vitro target validation is hampered by the difficulty of transfecting primary neuronal cultures and assaying the effects of genes on neuronal viability. Here we describe a rapid, sensitive and simple reporter-based assay for the validation of genes putatively associated with Aβ-mediated neurotoxicity, which can in principle be extended to the validation of targets in the context of other neuronal insults. The assay is suitable for the generation of robust and reproducible data in primary neuronal cultures allowing the dissection at a molecular level of complex pathways activated by the toxic insult in a cellular context that more closely represents the real disease situation.

Fishing for Drugs from Nature: Zebrafish as a Technology Platform for Natural Product Discovery

Emerging challenges within the current drug discovery paradigm are prompting renewed interest in natural products as a source of novel, bioactive small molecules. With the recent validation of zebrafish as a biomedically relevant model for functional genomics and in vivo drug discovery, the zebrafish bioassay-guided identification of natural products may be an attractive strategy to generate new lead compounds in a number of indication areas. Here, we review recent natural product research using zebrafish and evaluate the potential of this vertebrate model as a discovery platform for the systematic identification of bioactive natural products.

Impact of Novel Screening Technologies on Ion Channel Drug Discovery

Ion channels are a large superfamily of membrane proteins that pass ions across membranes. They are critical to diverse physiological functions in both excitable and nonexcitable cells and underlie many diseases. As a result, they are an important target class which is proven to be highly "druggable". However, for high throughput screening (HTS), ion channels are historically difficult as a target class due to their unique molecular properties and the limitations of assay technologies that are HTS-amendable. In this article, we describe the background of ion channels and current status and challenges for ion channel drug discovery, followed by an overview of both conventional and newly emerged ion channel screening technologies. The critical impact of such new technologies on current and future ion channel drug discovery is also discussed.

QSAR: dead or alive?

This perspective concerns the methods employed within the current drug discovery community to develop predictive quantitative structure-activity relationships (QSAR). Specifically, a number of cautions are provided which may circumvent misuse and misunderstanding of the technique. Ignorance of such caveats has led to a discouraging tendency of the methods to result in poorly predictive models. Among these pitfalls are the fondness with which we associate correlation with causation, the mesmerizing influence of large numbers of molecular descriptors, the incessant misuse of the leave-one-out paradigm, and finally, the QSAR enigma wherein model predictivity is not a necessary component of a model's usefulness.

The ubiquitin system, disease, and drug discovery

The ubiquitin system of protein modification has emerged as a crucial mechanism involved in the regulation of a wide array of cellular processes. As our knowledge of the pathways in this system has grown, so have the ties between the protein ubiquitin and human disease. The power of the ubiquitin system for therapeutic benefit blossomed with the approval of the proteasome inhibitor Velcade in 2003 by the FDA. Current drug discovery activities in the ubiquitin system seek to (i) expand the development of new proteasome inhibitors with distinct mechanisms of action and improved bioavailability, and (ii) validate new targets. This review summarizes our current understanding of the role of the ubiquitin system in various human diseases ranging from cancer, viral infection and neurodegenerative disorders to muscle wasting, diabetes and inflammation. I provide an introduction to the ubiquitin system, highlight some emerging relationships between the ubiquitin system and disease, and discuss current and future efforts to harness aspects of this potentially powerful system for improving human health.Republished from Current BioData's Targeted Proteins database (TPdb; ).

Learning the drug target‐likeness of a protein

Current drug discovery and development approaches rely extensively on the identification and validation of appropriate targets; for example, those with marketable and robust therapeutics. Wide-ranging efforts have been directed at this problem and various approaches have been developed to identify disease-associated genes as candidates. In this work, we show with statistical significance that successful drug targets, in addition to their linkage to disease, share common characteristics that are disease-independent. For example, marked differences in functional category, tissue specificity, and sequence variability are observed between known targets and average proteins. These results lead to an interesting hypothesis: potentially good drug targets shall have some desired properties, which we refer to as "drug target-likeness" that are beyond their disease-associations. Because of the limited availability of comprehensive protein characteristics data, we tried to learn the drug target-likeness property at the sequence level. Results show that a support vector machine model is able to accurately distinguish targets from nontargets entirely with sequence features. It is our hope that these encouraging results will invite future systematic proteomic scale experiments to gather necessary protein characteristics data for the accurate and predictive definition of "drug target-likeness", providing a new perspective toward understanding and pursuing effective therapeutics.

Target deconvolution strategies in drug discovery

Recognition of some of the limitations of target-based drug discovery has recently led to the renaissance of a more holistic approach in which complex biological systems are investigated for phenotypic changes upon exposure to small molecules. The subsequent identification of the molecular targets that underlie an observed phenotypic response--termed target deconvolution--is an important aspect of current drug discovery, as knowledge of the molecular targets will greatly aid drug development. Here, the broad panel of experimental strategies that can be applied to target deconvolution is critically reviewed.

Chemical Proteomics Identifies Unanticipated Targets of Clinical Kinase Inhibitors

Kinases represent one of the most important target classes of current drug discovery efforts. However, because the vast majority of potential small-molecule therapeutics is directed toward the highly conserved ATP-binding cleft, kinase inhibitors often exhibit significant unintended off-target effects. A recent report describes a chemical proteomics methodology that enables the simultaneous in vivo quantification of the on- and off-binding targets of kinase inhibitors across hundreds of nucleotide-dependent enzymes.

Editorial [Hot Topic: The Pros of Not Being Competitive (Allosteric Modulation of GPCRs) (Guest Editors: Vincent Mutel and Bernhard Bettler)

Drugs acting at G-protein coupled receptors (GPCRs) represent the core of modern medicine. Traditionally, these drugs target the orthosteric site of the receptors, i.e. the binding site of the endogenous agonist. An increasing number of patents describe synthetic allosteric modulators of GPCRs, which influence receptor activity at sites distinct from the orthosteric site. This documents that the search for allosteric modulators of GPCRs has become a fully-fledged part of current drug discovery efforts. It is now generally accepted that allosteric modulation of GPCRs holds considerable promise for the development of novel therapeutics, but it has taken decades to persuade the skeptics of the advantages this concept has to offer. Allosteric modulation is now considered a valid strategy to obtain first generation therapeutics as well as second generation alternatives to currently available therapeutics. A key step towards broad exploration of the allosteric concept was the introduction of cell-based functional high-throughput screening assays for GPCRs, which have replaced radioligand binding assays as the primary screen for allosteric compounds. The reviews in this special issue, written by some of the leading scientists in the field, provide an overview of the experimental strategies used to identify and characterize allosteric modulators for Class A, B, and C GPCRs.

Heparanase: a target for drug discovery in cancer and inflammation

The remodelling of the extracellular matrix (ECM) has been shown to be highly upregulated in cancer and inflammation and is critically linked to the processes of invasion and metastasis. One of the key enzymes involved in specifically degrading the heparan sulphate (HS) component of the ECM is the endo-beta-glucuronidase enzyme heparanase. Processing of HS by heparanase releases both a host of bioactive growth factors anchored within the mesh of the ECM as well as defined fragments of HS capable of promoting cellular proliferation. The finding that heparanase is elevated in a wide variety of tumor types and is subsequently linked to the development of pathological processes has led to an explosion of therapeutic strategies to inhibit its enzyme activity. So far only one compound, the sulphated oligosaccharide PI88, which both inhibits heparanase activity and has effects on growth factor binding has reached clinical trials where it has shown to have promising efficacy. The scene has clearly been set however for a new generation of compounds, either specific to the enzyme or with dual roles, to emerge from the lab and enter the clinic. The aim of this review is to describe the current drug discovery status of small molecule, sugar and neutralising antibody inhibitors of heparanase enzyme activity. Potential strategies will also be discussed on the selection of suitable biomarker strategies for specific monitoring of in vivo heparanase inhibition which will be crucial for both animal model and clinical trial testing.

Screening for transient biological interactions as applied to albumin ligands: A new concept for drug discovery

The notion that many biological interactions are based on transient binding (dissociation constants ( K d) in the range of 10–0.01 mM) is familiar, yet the implications for biological sciences have been realized only recently. An important area of biological sciences is drug design, where the traditional “lock and key” view of binding has prevailed and drug candidates are usually selected on their merits as being tight binders. However, the rationale that transient interactions are of importance for drug discovery is slowly gaining acceptance. These interactions may relate not only to the desired target interaction but also to unwanted interactions creating, for example, toxicity problems. Here we demonstrate, in a high-throughput screening format, affinity selection of weak binders to a model target of albumin by zonal retardation chromatography. It is perceived that this approach can define the “transient drug” as a complement to current drug discovery procedures.

Metallopeptide-promoted inactivation of angiotensin-converting enzyme and endothelin-converting enzyme 1: toward dual-action therapeutics

A series of metallopeptides based on the amino terminal copper/nickel (ATCUN) binding motif have been evaluated as classical inhibitors and catalytic inactivators of both rabbit and human angiotensin-converting enzyme (hACE), and human endothelin-converting enzyme 1 (hECE-1). The cobalt complex [KGHK-Co(NH3)2]2+, where KGHK is lysylglycylhistidyllysine, displayed similar K(I) and IC50 values to those found for [KGHK-Cu]+, in spite of the enhanced charge, and so either the influence of charge is offset by the steric influence of the axially coordinated ammine ligands, or binding is dominated by contributions from the amino acid side chains, especially the C-terminal lysine that mimics the binding pattern observed for lisinopril. Moreover, the inhibition observed for [KGHK-Co(NH3)2]2+ contrasts with the activation of hACE by Co2+(aq), reflecting the stimulation of enzyme activity following replacement of the catalytic zinc cofactor by cobalt ion at each of the two active sites. Quantitative analysis of the dose-dependent stimulation of activity by Co2+(aq) yielded apparent affinities of 1.3 +/- 0.2 and 56 +/- 8 microM for the two sites in the presence of saturating Zn2+ (10 microM). Catalytic inactivation of hACE by [KGHK-Cu]+ at subsaturating concentrations had previously been characterized, with k(obs) = 2.9 +/- 0.5 x 10(-2) min(-1). Under similar conditions, the same complex is found to catalytically inactivate hECE-1, with k(obs) = 2.12 +/- 0.16 x 10(-2) min(-1), demonstrating the potential for dual-action activity against two key drug targets in cardiovascular disease. Irreversible inactivation of a drug target represents a novel mechanism of drug action that complements existing classical inhibitor strategies that underlie current drug discovery efforts.

High throughput screening in drug discovery

Drug discovery is a highly complex and multidisciplinary process which goal is to identify new antitumoral drugs. The screening attrition rate in the current drug discovery protocols suggests that one marketable drug emerges from approximately one million screened compounds. This leads to pressure to screen larger libraries in order to continue the pipeline and to the development of High Throughput Screening. HTS is only a name for specific developments in laboratory automation to collect a large amount of experimental data in a relatively short time. HTS can test hundreds of thousands of compounds per day, however, if fewer compounds could be tested without compromising the probability of success, the cost and time would be greatly reduced. To that end, new developments in large-scale cell biology and compound library design in silico have evolved to obtain data with higher predictability of clinical efficacy.

Receptor‐Assisted Combinatorial Chemistry: Thermodynamics and Kinetics in Drug Discovery

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Non-Monoamine-Based Approach for the Treatment of Depression and Anxiety Disorders

Although currently prescribed antidepressants with actions mediated through alteration of monoaminergic transmission have been proven to be useful for the treatment of depressive and anxiety disorders, they are far from ideal due to their slow onset of action and low rate of responses. Although the brain monoamine systems have long been the focus of drug therapy for depression and anxiety disorders, current drug discovery has aimed at new molecular targets outside the monoamine systems to overcome these problems. Recent increase in understanding of the molecular mechanisms of depression and anxiety has provided alternative molecular targets for these disorders. In particular, receptors within the glutamate, gamma-aminobutyric acid and neuropeptide systems provide a diversity of drug targets, and molecular biological and behavioral studies of these receptors have revealed the important roles they play in depression and anxiety. Here, we review recent patents and advances in research on these emerging molecular targets for the treatment of depression and anxiety, and discuss their advantages over currently used antidepressants and anxiolytics.