Drug Discovery Technologies Research Articles

Chemoenzymatic Synthesis of Small Molecule Human Therapeutics

Pharmaceuticals have historically been produced by either chemical synthesis or whole cell fermentation. The former is applied to synthetic small molecules while the latter to natural products. As a result of recent advances in rapid discovery of enzymes through genome mining and metagenomics, and their tunability in functions and stability through directed evolution, biocatalysis is emerging to be a transformational technology for drug discovery and production. Enzymes can catalyze reactions otherwise challenging by chemical approaches. Furthermore, enzymatic catalysis is a powerful tool for green chemistry development. This manuscript gives a brief overview of current status in integrating chemical and biological transformations for the synthesis of small molecular therapeutics.

The Race for Chemical and Biological Space: Drug Discovery and Innovative Technologies

Chemical Biology & Drug DesignVolume 73, Issue 1 p. 1-2 The Race for Chemical and Biological Space: Drug Discovery and Innovative Technologies Tomi K. Sawyer, Tomi K. Sawyer Editor-in-Chief, Chemical Biology & Drug DesignChief Scientific Officer and Senior Vice-President,Drug Discovery and Innovative Technologies,Aileron Therapeutics, Cambridge, Massachusetts, USAAdjunct Professor, Department of Chemistry,University of Massachusetts, Amherst, Massachusetts, USAAdjunct Professor, Biochemistry & Molecular BiologyUniversity of Massachusetts, Amherst, Massachusetts, USAAdjunct Professor, Department of Cancer Biology,University of Massachusetts Medical School, Worcester, Massachusetts, USAAdjunct Professor, Center for Drug Discovery,Northeastern University, Boston, Massachusetts, USAOrganizing Chair, World Project for Chemical Biology and Drug DesignSearch for more papers by this author Tomi K. Sawyer, Tomi K. Sawyer Editor-in-Chief, Chemical Biology & Drug DesignChief Scientific Officer and Senior Vice-President,Drug Discovery and Innovative Technologies,Aileron Therapeutics, Cambridge, Massachusetts, USAAdjunct Professor, Department of Chemistry,University of Massachusetts, Amherst, Massachusetts, USAAdjunct Professor, Biochemistry & Molecular BiologyUniversity of Massachusetts, Amherst, Massachusetts, USAAdjunct Professor, Department of Cancer Biology,University of Massachusetts Medical School, Worcester, Massachusetts, USAAdjunct Professor, Center for Drug Discovery,Northeastern University, Boston, Massachusetts, USAOrganizing Chair, World Project for Chemical Biology and Drug DesignSearch for more papers by this author First published: 18 December 2008 https://doi.org/10.1111/j.1747-0285.2008.00760.xCitations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume73, Issue1January 2009Pages 1-2 RelatedInformation

Preimplantation genetic diagnosis as a source of human embryonic stem cells for disease research and drug discovery

Embryos surplus to therapeutic requirements following preimplantation genetic diagnosis can be used to derive human embryonic stem cell (hESC) lines carrying mutations significant to human disease. These cells provide a powerful in vitro tool for modelling disease progression in a number of cell types as well as having the potential to revolutionise drug discovery. Robust and reproducible directed differentiation protocols are needed to maximise the potential of these cells. In this review, we explore the current use of hESC and induced pluripotent stem cells in disease-specific research and discuss the use of stem cell technology in drug discovery and toxicity testing.

Teva Invests in Yeast-based Drug Discovery Technology

Pharmaceutical strategic business consultancy involved in partnering, licensing, acquisitions, divestments and new business start-ups. We assist in due diligence and write expert reports for investors. We are experts in business intelligence and markets

SNP Technologies for Drug Discovery: A Current Review

Single nucleotide polymorphisms (SNPs) are unique genetic differences between individuals that contribute in significant ways to the determination of human variation including physical characteristics like height and appearance as well as less obvious traits such as personality, behaviour and disease susceptibility. SNPs can also significantly influence responses to pharmacotherapy and whether drugs will produce adverse reactions. The development of new drugs can be made far cheaper and more rapid by selecting participants in drug trials based on their genetically determined response to drugs. Technology that can rapidly and inexpensively genotype thousands of samples for thousands of SNPs at a time is therefore in high demand. With the completion of the human genome project, about 12 million true SNPs have been identified to date. However, most have not yet been associated with disease susceptibility or drug response. Testing for the appropriate drug response SNPs in a patient requiring treatment would enable individualised therapy with the right drug and dose administered correctly the first time. Many pharmaceutical companies are also interested in identifying SNPs associated with polygenic traits so novel therapeutic targets can be discovered. This review focuses on technologies that can be used for genotyping known SNPs as well as for the discovery of novel SNPs associated with drug response.

Design, Synthesis And Evaluation Of Constrained Methoxyethyl (cMOE) and Constrained Ethyl (cEt) Nucleoside Analogs

Antisense drug discovery technology is a powerful method to modulate gene expression in animals and represents a novel therapeutic platform.(1) We have previously demonstrated that replacing 2'O-methoxyethyl (MOE, 2) residues in second generation antisense oligonucleotides (ASOs) with LNA (3) nucleosides improves the potency of some ASOs in animals. However, this was accompanied with a significant increase in the risk for hepatotoxicity.(2) We hypothesized that replacing LNA with novel nucleoside monomers that combine the structural elements of MOE and LNA might mitigate the toxicity of LNA while maintaining potency. To this end we designed and prepared novel nucleoside analogs 4 (S-constrained MOE, S-cMOE) and 5 (R-constrained MOE, R-cMOE) where the ethyl chain of the 2'O-MOE moiety is constrained back to the 4' position of the furanose ring. As part of the SAR series, we also prepared nucleoside analogs 7 (S-constrained ethyl, S-cEt) and 8 (R-constrained Ethyl, R-cEt) where the methoxymethyl group in the cMOE nucleosides was replaced with a methyl substituent. A highly efficient synthesis of the nucleoside phosphoramidites with minimal chromatography purifications was developed starting from cheap commercially available starting materials. Biophysical evaluation revealed that the cMOE and cEt modifications hybridize complementary nucleic acids with the same affinity as LNA while greatly increasing nuclease stability. Biological evaluation of oligonucleotides containing the cMOE and cEt modification in animals indicated that all of them possessed superior potency as compared to second generation MOE ASOs and a greatly improved toxicity profile as compared to LNA.

In vitro analysis of a hepatic device with intrinsic microvascular-based channels

A novel microfluidics-based bilayer device with a discrete parenchymal chamber modeled upon hepatic organ architecture is described. The microfluidics network was designed using computational models to provide appropriate flow behavior based on physiological data from human microvasculature. Patterned silicon wafer molds were used to generate films with the vascular-based microfluidics network design and parenchymal chamber by soft lithography. The assembled device harbors hepatocytes behind a nanoporous membrane that permits transport of metabolites and small proteins while protecting them from the effects of shear stress. The device can sustain both human hepatoma cells and primary rat hepatocytes by continuous in vitro perfusion of medium, allowing proliferation and maintaining hepatic functions such as serum protein synthesis and metabolism. The design and fabrication processes are scalable, enabling the device concept to serve as both a platform technology for drug discovery and toxicity, and for the continuing development of an improved liver-assist device.

Label-Free Cell-Based Assays for GPCR Screening

G protein-coupled receptors (GPCRs) have been proven to be the largest family of druggable targets in the human genome. Given the importance of GPCRs as drug targets and the de-orphanization of novel targets, GPCRs are likely to remain the frequent targets of many drug discovery programs. With recent advances in instrumentation and understanding of cellular mechanisms for the signals measured, biosensor-centered label-free cell assay technologies become a very active area for GPCR screening. This article reviews the principles and potential of current label-free cell assay technologies in GPCR drug discovery.

Supramolecular Chiro-Biomedical Assays and Enantioselective HPLC Analyses for Evaluation of Profens as Non-Steroidal Anti-Inflammatory Drugs, Potential Anticancer Agents and Common Xenobiotics

The permanent world-wide increase in therapeutic administration of racemic profens as easy available non-prescribed analgesic drugs and a common first-choice anti-inflammatory agents was recently linked with renewed interest in their beneficial use, also as enantiopure formulations, to treat and/or prevent a variety of human malignancies including its four major types as colorectal, breast, lung, and prostate cancer. This underlies the continuous need of selecting perfectly suited chiral separation methods of profens capable to determine nanolevels of a distomer in presence of the eutomer in a variety of complex biological and environmental media. Thus, current improvements for direct enantiomeric separations of profens by well defined supramolecular-based chiral HPLC and recently developed monolithic, combinatorial, bimodal and polymeric chiral stationary phases employing a modern supramolecular chirality concepts has been outlined in this review. The use of diverse supramolecular approaches for chiral HPLC as an easy accessible tool enabling fast development of nanoscale enantioselective, high-throughput and gradient screening procedures for in situ monitoring of stereoselective ADME properties of profens in range of anticancer drug discovery technologies has been also addressed.

Chemical synthesis in nanosized cavities

This account briefly discusses methods of in-cavity synthesis with the main focus on molecularly imprinted polymers and self-assembled capsules. Discussed are examples that highlight recent progress and outline key challenges for the further development of in-cavity synthesis. Emphasis is intentionally placed at potential applications in drug discovery and combinatorial technologies.

Natural Products as a Robust Source of New Drugs and Drug Leads: Past Successes and Present Day Issues

The history of drug development has its foundation firmly set in the study of natural remedies used to treat human disease over centuries. Analysis of medicinal plants, bioactive cultures, and increased understanding of micronutrients in the food chain opened the door to the development of purified and defined chemical compounds as dose-controlled medicines. Thus, with the early discovery of cardiotonics in foxglove, salicylic acid in willow bark, morphine in poppies, and penicillin in mold, the pharmaceutical industry was launched. Such natural small molecules served as treatments for disease and ultimately, as pharmacologic tools to enable the understanding of the biochemical pathways and mechanisms of disease. In contrast, modern drug discovery technologies coupled with the powerful tools of biotechnology have prompted drug discovery organizations to focus on target-driven drug discovery at the molecular level by launching high-throughput screening programs using artificial biochemical assays. At a time when the pharmaceutical industry has come under scrutiny for high rates of drug development failure, it is interesting to see that natural products drug discovery has been marginalized in favor of this high-throughput biochemical screening paradigm. If modern drug development is once again to benefit from natural products as a source, then the limitations of artificial biochemical assays as applied to the screening of natural extracts must be realized in order to capitalize on the vast natural molecular diversity and rich ethnobotanic data that has emerged worldwide. Natural compounds can again become central players in the treatment of disease and in the understanding of disease mechanisms.

The application of cell‐based label‐free technology in drug discovery

Cell-based assays are an important part of the drug discovery process allowing for interrogation of targets and pathways in a more physiological setting compared to biochemical assays. One of the main hurdles in the cell-based assay field is to design sufficiently robust assays with adequate signal to noise parameters while maintaining the inherent physiology of the pathway or target being investigated. Conventional label and reporter-based cell assays may be more prone to artifacts due to considerable manipulation of the cell either by the label or over-expression of targets or reporter proteins. Cell-based label-free technologies preclude the need for cellular labeling or over-expression of reporter proteins, utilizing the inherent morphological and adhesive characteristics of the cell as a physiologically relevant and quantitative readout for various cellular assays. Furthermore, these technologies utilize non-invasive measurements allowing for time resolution and kinetics in the assay. In this article, we have reviewed the various label-free technologies that are being used in drug discovery settings and have focused our discussion on impedance-based label-free technologies and its main applications in drug discovery.

Current In Vitro Kinase Assay Technologies: The Quest for a Universal Format

The rapidly growing interest in kinases as drug targets has prompted the development of many kinase assay technologies. These technologies can be grouped into three categories: radiometric assays, phospho-antibody-dependent fluorescence/luminescence assays, and phospho-antibody-independent fluorescence/luminescence assays. This article will review some of the major kinase assay technologies on the market, with particular emphasis on the newest systems. We will describe the physical principles, the practical advantages and drawbacks, and the potential applications of these technologies in kinase drug discovery. Most of these technologies are suitable for HTS, but only a few can be utilized for kinetic and mechanistic studies. Significant progress towards development of generic assays, free of radioisotopes and custom reagents such as phospho-specific antibodies, has been made in recent years. However, due to various limitations of each format, none of these generic assay technologies can yet claim to be truly universal. Several factors, including the intended applications, cost, timeline, expertise, familiarity, and comfort level, should be considered prior to pursuing a particular kinase assay technology.

Riboswitches as new antibiotics targets

New cellular targets are needed to reinvigorate antibacterial drug discovery. This need could potentially be filled by riboswitches—messenger RNA (mRNA) structures that regulate gene expression in bacteria. Riboswitches are unique from other RNAs that serve as drug targets in that they have evolved to form structured and highly selective receptors for small drug‐like metabolites. In most cases, metabolite binding to the receptor represses the expression of the gene or genes coded by the mRNA. If a new metabolite analog were designed that binds to the receptor, the gene(s) regulated by that riboswitch could be repressed, with a potentially lethal effect to the bacteria. Recent work suggests that certain antibacterial compounds discovered decades ago function at least in part by targeting riboswitches. Herein we will summarize the experiments validating riboswitches as drug targets, describe the existing technology for riboswitch drug discovery, and discuss the challenges that may face riboswitch drug discoverers.

The Use of AlphaScreen Technology in HTS: Current Status

AlphaScreen (Amplified Luminescent Proximity Homogeneous Assay Screen) is versatile assay technology developed to measuring analytes using a homogenous protocol. This technology is an example of a bead-based proximity assay and was developed from a diagnostic assay technology known as LOCI (Luminescent Oxygen Channeling Assay). Here, singlet oxygen molecules, generated by high energy irradiation of Donor beads, travel over a constrained distance (approx. 200 nm) to Acceptor beads. This results in excitation of a cascading series of chemical reactions, ultimately causing generation of a chemiluminescent signal.In the past decade, a wide variety of applications has been reported, ranging from detection of analytes involved in cell signaling, including protein:protein, protein:peptide, protein:small molecule or peptide:peptide interactions. Numerous homogeneous HTS-optimized assays have been reported using the approach, including generation of second messengers (such as accumulation of cyclic AMP, cyclic GMP, inositol [1, 4, 5] trisphosphate or phosphorylated ERK) from liganded GPCRs or tyrosine kinase receptors, post-translational modification of proteins (such as proteolytic cleavage, phosphorylation, ubiquination and sumoylation) as well as protein-protein and protein-nucleic acid interactions.Recently, the basic AlphaScreen technology was extended in that the chemistry of the Acceptor bead was modified such that emitted light is more intense and spectrally defined, thereby markedly reducing interference from biological fluid matrices (such as trace hemolysis in serum and plasma). In this format, referred to as AlphaLISA, it provides an alternative technology to classical ELISA assays and is suitable for high throughput automated fluid dispensing and detection systems.Collectively, AlphaScreen and AlphaLISA technologies provide a facile assay platform with which one can quantitate complex cellular processes using simple no-wash microtiter plate based assays. They provide the means by which large compound libraries can be screened in a high throughput fashion at a diverse range of therapeutically important targets, often not readily undertaken using other homogeneous assay technologies. This review assesses the current status of the technology in drug discovery, in general, and high throughput screening (HTS), in particular.

Editorial [Hot Topic: Imaging Science and Technology in Drug Discovery (Guest Editor: David J. Yang)

Editorial [Hot Topic: Imaging Science and Technology in Drug Discovery (Guest Editor: David J. Yang)

The Baculovirus Display Technology - An Evolving Instrument for Molecular Screening and Drug Delivery

High throughput screening is a core technology in drug discovery. During the past decade, several strategies have been developed to screen (poly)peptide libraries for diverse applications including disease diagnosis and profiling, imaging, as well as therapy. The recently established baculovirus display vector system (BDVS) represents a eukaryotic screening platform that combines the positive attributes of both cell and virus-based display approaches, allowing presentation of complex polypeptides on cellular and viral surfaces. Compared to microbial display systems, the BDVS has the advantage of correct protein folding and post-translational modifications similar to those in mammals, facilitating expression and analysis of proteins with therapeutic interest. The applicability of the system is further expanded by the availability of genetically engineered insect cell lines capable of performing e.g. mammalianized glycosylation in combination with high level of expression. In addition to insect cells, baculovirus can mediate delivery and expression of heterologous genes in a broad spectrum of primary and established mammalian cells. Currently, a variety of baculovirus-based assays aiming at routine high throughput identification of agents targeting cell surface receptors or studies on ligand-receptor interactions are under construction. Here, the advancements and future prospects of the baculovirus display technologies with emphasis on molecular screening and drug delivery applications using insect cell display, mammalian cell display, and virion display are described.

Establishing a multicellular model by three-dimensional cell-assembly technique for metabolic syndrome

AbstractOne of the major obstacles in developing multifunctional drugs for the metabolic syndrome (MS) is lack of in vitro models that capture more complex features of the disease. Here we give the first report that establishes an energy metabolic system model using cell-assembly technique which can assemble cells into designated places to form complex three-dimensional structures. Adipose-derived stromal cells were assembled and induced differentiation into adipocytes and endothelial cells; pancreatic islets were then deposited at designated locations and constituted adipoinsular axis with adipocytes. Analysis of the factors involved in energy metabolism showed our system could capture more physiological and pathophysiological features of the in vivo energy metabolism. Drugs known to have effects on MS showed accordant effects in the systems. Construction and study of such multicellular systems could help us better understand pathogenesis of MS, develop new technologies for drug discovery, and foster applications in tissue engineering and metabolomics profiling.

Virtual Screening and Its Integration with Modern Drug Design Technologies

Drug discovery is a highly complex and costly process, which demands integrated efforts in several relevant aspects involving innovation, knowledge, information, technologies, expertise, R&D investments and management skills. The shift from traditional to genomics- and proteomics-based drug research has fundamentally transformed key R&D strategies in the pharmaceutical industry addressed to the design of new chemical entities as drug candidates against a variety of biological targets. Therefore, drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein-ligand interactions. The combination of available knowledge of several 3D protein structures with hundreds of thousands of small-molecules have attracted the attention of scientists from all over the world for the application of structure- and ligand-based drug design approaches. In this context, virtual screening technologies have largely enhanced the impact of computational methods applied to chemistry and biology and the goal of applying such methods is to reduce large compound databases and to select a limited number of promising candidates for drug design. This review provides a perspective of the utility of virtual screening in drug design and its integration with other important drug discovery technologies such as high-throughput screening (HTS) and QSAR, highlighting the present challenges, limitations, and future perspectives in medicinal chemistry.

創薬初期の安全性評価における質量分析の活用

Recent advances in drug discovery technologies require a paradigm shift in safety evaluation of drug candidates, especially with respect to their toxicological contribution at the early stage of drug discovery. In this context, new sciences and technologies should be implemented in the field of safety evaluation, and the numerous applications of mass spectrometry (MS) are thought to be one of the key approaches. In the present review, we have summarized the usability of MS and its practical applications in early safety evaluation.