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Drug & disease targets glossary & taxonomy
Evolving Terminologies for Emerging Technologies
Comments? Questions? Revisions?
Mary Chitty MSLS
Last revised June 24, 2019


SCOPE NOTE: Drug targets include Chimeric Antigen Receptors CAR-T, GPCRs G protein coupled receptors, ion channels, kinases, membrane proteins, protease inhibitors, ubiquitin 

Drug targets A prerequisite for counting the number of targets is defining what a target is. Indeed, this is the crucial, most difficult and also most arbitrary part of the present approach. For the purpose of this paper, we consider a target to be a molecular structure (chemically definable by at least a molecular mass) that will undergo a specific interaction with chemicals that we call drugs because they are administered to treat or diagnose a disease. The interaction has a connection with the clinical effect(s).  This definition implies several constraints. First, the medicinal goal excludes pharmacological and biochemical tools from the present approach. Second, a major constraint is a lack of technique. Life, including disease, is dynamic, but as we do not yet directly observe the interactions of drugs and targets, and only partly notice the subsequent biochemical 'ripples' they produce; we are generally limited to 'still life' (for example, X-ray crystal structures) and to treating targets as static objects. In the case of G-protein-coupled receptors (GPCRs), the pharmaceutically most useful class of receptors, a re-organization of the protein after drug binding was derived from biochemical data4, but such approaches are still in their infancy. Nature Reviews Drug Discovery 5, 821-834 (October 2006) doi:10.1038/nrd2132   OPINION: Drugs, their targets and the nature and number of drug targets Peter Imming1, Christian Sinning1 & Achim Meyer1

Related glossaries include:  Drug discovery & development     Molecular Diagnostics
Biology  Functional genomics      Pharmaceutical biology      SNPs and other genetic variations  
Chemistry  Assays & Screening     Cheminformatics      Libraries & Synthesis     Pharmaceutical chemistry  
Informatics: Drug discovery informatics     Bioinformatics     Cheminformatics     Genomic Informatics    Protein Informatics  
Technologies Gene amplification & PCR     Genomic Technologies      Metabolic profiling      Microarrays & protein arrays      Molecular Imaging      Protein Technologies      Sequencing

Agonist Immunotherapy Targets April 11-12, 2019 Boston, MA Program | Stepping on the Gas with Costimulatory Agents The immunotherapies industry is currently dominated by antagonist antibodies such as PD-1 and CTLA-4. However, it is clear that antagonists alone are not enough to elicit response in the majority of patients, hence a rising interest in agonists targets.  CHI’s Agonist Immunotherapy Targets conference will examine these modalities and their treating disease. Agonists showing the most promise, including OX40, CD27, GITR, and 4-1BB, will be covered in clinical case studies by examining the data as well as the biology and mechanisms. Emerging agonists, including TNFR receptors, ICOS, STING, and VISTA will also be discussed. Focus will be given throughout to potential combination immunotherapies to ensure durable antitumor response.

allosteric modulators: Allosteric modulation of GPCRs is rapidly emerging as a major area of interest for pharmaceutical discovery because allosteric modulators have the potential to show dramatically improved safety, tolerance, and side-effect profiles compared to traditional orthosteric agonists and antagonists.

autophagy:  Emerging ubiquiting & autophagy targets September 17-18 2019 Boston, MA  Autophagy and the ubiquitin-proteasome system (UPS) are the two major pathways responsible for protein degradation and maintenance of cellular homeostasis. They consist of well-controlled, selective mechanisms for intracellular protein degradation and turnover. New understanding of the role and molecular mechanisms involved in the dysregulation of autophagy and ubiquitin pathways has revealed its underlying role in cancer, CNS, immunology and other diseases. However, the diversity of substrates and the multi-step processes involved, make it difficult to target these pathways for therapeutic intervention. In recent years, the development of high-quality chemical probes, small molecule modulators, assays and screening platforms have helped identify novel autophagy and ubiquitin targets for drug discovery. 

biological target: A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets are proteins and nucleic acids. The definition is context-dependent, and can refer to the biological target of a pharmacologically active drug compound, the receptor target of a hormone (like insulin), or some other target of an external stimulus. Biological targets are most commonly proteins such as enzymesion channels, and receptors. Wikipedia accessed 2018 Aug 22   See also  Drug discovery informatics drug design 

cancer cell metabolism: The fact that cancer cells have an altered glucose metabolism has sparked new interest in the pharmaceutical industry. Reversing the increased glucose consumption in cancer cells is an important step and has great potential for therapeutic drug developments.

channel blocker,  Compound that reduces or eliminates the conductance of an ion channel by impeding the movement of ions through that channel  Note: Dihydropyridine antagonists such as nifedipine, which also block the conductance of some L-type calcium channels, are not classified as channel blockers since their action is to inhibit channel gating. Example: verapamil, which blocks the conductance of some L-type calcium channels. IUPAC Glossary Biomolecular Screening   See related ion channels.

See also  Biologics  CARs Chimeric Antigen Receptors

Constrained Peptides and Macrocyclics September 26-27, 2018 Boston, MA Program | Constrained peptides covers the progress and challenges of accessing new chemical space – the middle space – to find molecules with drug potential that are bigger than small molecules but smaller than biologics. The hope is that these middle-sized molecules are big enough for more specific interactions with protein-protein interaction surfaces but small enough to penetrate the cell, reach intracellular drug targets and be orally bioavailable. However, theory is still meeting practice. Researchers continue to refine the ’rules’ and properties for the best design of this class of molecules which mainly consist of constrained peptides and synthetic macrocyclics.

cytoplasmic and nuclear receptors: Proteins in the cytoplasm or nucleus that specifically bind signaling molecules and trigger changes which influence the behavior of cells. The major groups are the steroid hormone receptors (RECEPTORS, STEROID), which usually are found in the cytoplasm, and the thyroid hormone receptors (RECEPTORS, THYROID HORMONE), which usually are found in the nucleus. Receptors, unlike enzymes, generally do not catalyze chemical changes in their ligands. MeSH, 1994

Discovery on Target
Discovery on Target Sept 16-19, 2019 • Boston, MA Program  Novel drug targets and technologies
for mall molecules and biologics.

disease targets:
The critical strategy for a pharmaceutical company going forward is one that uses pharmacogenomics and biomedical informatics to better define disease targets. ...  Pharmacogenomics is key to gaining a better definition of disease, a better stratification of patients and improved disease staging. Until these are clear, and until some form of biomedical informatics is put into place, therapeutic design is going to be flawed by poorly defined targets. Broader term: target Related term: drug target  

drug target, drug targets:  An unspoken industry rule alleges that at least 50% of published studies from academic laboratories cannot be repeated in an industrial setting, wrote venture capitalist Bruce Booth in a recent blog post. A first-of-a-kind analysis of Bayer's internal efforts to validate 'new drug target' claims now not only supports this view but suggests that 50% may be an underestimate; the company's in-house experimental data do not match literature claims in 65% of target-validation projects, leading to project discontinuation. Nature Reviews Drug Discovery 10, 643-644 (September 2011) | doi:10.1038/nrd3545 Reliability of 'new drug target' claims called into question Asher Mullard

Good drugs are potent and specific; that is, they must have strong effects on a specific biological pathway and minimal effects on all other pathways. Confirmation that a compound inhibits the intended target (drug target validation) and the identification of undesirable secondary effects are among the main challenges in developing new drugs. Matthew J. Morton et. al, Drug target validation and identification of secondary drug target effects using DNA Microarrays,  November 1998 4 (11): 1293 - 1301, Nov. 1998  Related terms:  molecular drug targets, target families. Narrower terms: gene target, protein target. targets  

How many drug targets are there? John P Overington, et. al, Nature Reviews Drug Discovery, 2006 

drug targeting: Drug delivery

drug targets map The success of mechanism-based drug discovery depends on the definition of the drug target. This definition becomes even more important as we try to link drug response to genetic variation, understand stratified clinical efficacy and safety, rationalize the differences between drugs in the same therapeutic class and predict drug utility in patient subgroups. However, drug targets are often poorly defined in the literature, both for launched drugs and for potential therapeutic agents in discovery and development. Here, we present an updated comprehensive map of molecular targets of approved drugs. We curate a total of 893 human and pathogen-derived biomolecules through which 1,578 US FDA-approved drugs act. These biomolecules include 667 human-genome-derived proteins targeted by drugs for human disease. Analysis of these drug targets indicates the continued dominance of privileged target families across disease areas, but also the growth of novel first-in-class mechanisms, particularly in oncology. We explore the relationships between bioactivity class and clinical success, as well as the presence of orthologues between human and animal models and between pathogen and human genomes. A comprehensive map of molecular drug targets Rita Santos  , Oleg UrsuAnna GaultonA. Patrícia BentoRamesh S. DonadiCristian G. Bologa , Anneli KarlssonBissan Al-LazikaniAnne HerseyTudor I. Oprea  & John P. Overington Nature Reviews Drug Discovery volume16, pages19–34 (2017) |  

drug transporters: What are usually considered to be ‘multispecific drug transporters’ come from two transporter superfamilies: the solute carrier (SLC) transporters and the ATP-binding cassette (ABC) transporters1. Because they have a crucial role in absorption, distribution, metabolism and elimination (ADME), these drug transporters are of considerable pharmacological significance (TABLE 1); indeed, owing to recent regulatory interest, the focus on these transporters has intensified16. What do drug transporters really do?. Nat Rev Drug Discov. 2014;14(1):29-44.

DrugBank: The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug data with comprehensive drug target information.

druggable targets: a protein, peptide, or nucleic acid with activity that can be modulated by a drug, which can consist of a small molecular weight chemical compound (SMOL) or a biologic [BIOL) such as an antibody or recombinant protein (Table 1). Isabella Gashaw, Peter Ellinghaus, Anette Sommer, Khrusru Asadullah "What makes a good drug target" Drug Discovery Today 2011 Dec;16(23-24):1037-43. Epub 2011 Sep 16.

"We have historically fewer innovative targets per year", said Christopher Lipinski, formerly of Pfizer, showing that only 24 innovative drugs with new targets have been launched between 1994 and 2001 "Many more druggable targets may have emerged in these eight years, but there are not enough druglike molecules to match them", Lipinski said. Horizon Symposia 4 Charting Chemical Space, 2004   See also druggability: Drug discovery   Compare undruggable targets

efficacy targets: Molecular targets through which the drug mediates its approved therapeutic activities. John P Overington et. al How many drug targets are there? Nature Reviews Drug Discovery, 5 (12): 993-996 Dec 2006 

epigenetic targets: In the light of increasing knowledge on the role epigenetic factors play in disease, it is now becoming apparent that epigenetics could be ideal therapeutic targets - particularly taking into consideration that many of these epigenetic factors are reversible. Epigenetic drugs are incredibly potent and can help reverse abnormal gene expression that can result in various diseases.  BioMedCentral Blog 2016   Histone deacetylases (HDAC) are a class of enzymes that remove acetyl groups from an amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. … HDACs are downstream targets of signaling pathways, and signaling molecules (kinases in particular) regulate the activities of HDACs through multiple diverse pathways. HDACs in turn modulate different signaling pathways by deacetylation of histones and non-histones or through as yet unknown mechanisms. Proper coordination of cell signaling with histone/non-histone deacetylation is critical to precisely regulate both gene expression and a number of transcription independent events. HDAC proteins are vital regulators of fundamental cellular events, such as cell cycle progression, differentiation, and tumorigenesis. Abnormal HDACs can contribute to many different human diseases including cancer, neurodegenerative disorders, cardiac hypertrophy, and pulmonary diseases. Edward Seto, Xiang-Jiao Yang, in Handbook of Cell Signaling (Second Edition), 2010

gene target: Having identified a potential gene target (and, by inference, its protein product), one may wish to: (a) sequence the gene in a large number of affected and normal individuals to identify functional and diagnostic polymorphisms associated with the disease; or (b) rapidly screen the protein product for interactions with entities within the chemical portfolio of the company. Clearly, these needs are addressed by very different approaches and technological platforms, all of which may be defined as high throughput genomic strategies. 

gene targeting: The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. MeSH, 1995  

G-protein-coupled receptors GPCRs: GPCR-Based Drug Discovery September 18-19, 2019 Boston, MA Program |
G protein-coupled receptors (GPCRs), which relay chemical signals such as hormones from outside to the inside of cells, are the targets of approximately a third of the medicines on the market today. However, many of the GPCR-acting medicines were discovered decades or more ago, without today’s more detailed knowledge about and tools for working with GPCRs. The receptors span the membrane seven times, thus are challenging to solubilize and study in vitro. Recent biophysical advances though have bypassed some of the membrane-embedded challenges and enabled GPCR structural insights and spurred new screening applications. The receptors’ signaling complexities due to their ability to couple to a variety of G proteins (biased signaling) are also now more understood and capitalized upon to design more selective drugs/

GPCRs & Membrane Proteins Designing Drugs Targeted at Proteins with Multiple Membrane-Spanning Domains  APRIL 10-11, 2019 San Diego CA Cell surface complex membrane proteins such as G protein-coupled receptors (GPCRs), ion channels and transporters are attractive targets to design or discover drug agents against. They play important physiological roles and are accessible to compounds circulating in the body, including potential new drug agents. However, due to their membrane-embedded nature, this drug target class is less tractable to structure-based drug design approaches that rely on solubilization of the proteins to obtain X-ray crystal structures. However, genetic ‘tricks’ that facilitate solubilization, better biophysical tools that enable study of proteins while still in the membrane and advances in electron microscopy are speeding progress in rational drug design and screening efforts against complex membrane proteins.

The largest family of cell surface receptors  involved in SIGNAL TRANSDUCTION. They share a common structure and signal through HETEROTRIMERIC F- PROTEINS  MeSH 2004 "receptors, g-protein coupled".
Narrower terms: orphan G- protein coupled receptors, GPCRomics

histone demethylases: The genetic abnormalities that drive tumorigenesis are usually coupled with epigenetic alterations, such as DNA methylation and aberrant histone modifications, which may help oncogenic drivers accelerate cancer progression, metastasis, and therapy resistance. The discovery of histone demethylases has provided us new insight for understanding the epigenetic landscape of the chromatin environment of cancer cells. This review aims to summarize the current knowledge on the human histone lysine demethylases and their functions in cancers, and recent advances in development of small molecule inhibitors to target histone demethylases in cancer treatment. D'Oto A, Tian QW, Davidoff AM, Yang J. Histone demethylases and their roles in cancer epigenetics. J Med Oncol Ther. 2016;1(2):34-40.

Inflammation and Autoimmune Inhibitors  April 10-11, 2019 • San Diego, CA Program | Efforts to find and develop small molecule-based drug agents for combatting inflammation and autoimmune-related conditions is intensifying in the drug discovery industry. The first oral-based treatment for rheumatoid arthritis, a small molecule JAK kinase inhibitor, was launched a few years ago. The focus on oral-based anti-inflammatory agents (which are mostly small molecules though some macrocyclics and constrained peptides can also penetrate cells) is not only because oral-based therapeutics afford greater patient convenience, but also because of the rapidly accumulating scientific knowledge of the myriad of intracellular molecules involved in inflammation and autoimmune-related conditions.

ion channels:
Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. MeSH 1979 

Enable ions to flow rapidly through membranes in a thermodynamically downhill direction after an electrical or chemical impulse. IUPAC Bioinorganic

kinase inhibitors: Kinase Inhibitor Chemistry APRIL 9-10, 2019 San diego CA Over the past decade, kinase drug discovery has resulted in the rapid development of a new generation of anti-cancer drugs. As kinase inhibitor discovery remains an active area for a significant portion of all efforts, developers have found new ways to expand into a deeper portion of target space within the human kinome, moved beyond cancer and into chronic disease indications such as CNS disorders, as well as shifted toward allosteric modulation and harnessing slow-off or irreversible compounds.

Kinase Inhibitor Discovery September 18-19, 2019 Boston, MA Program | The human kinome is a very large and druggable class of targets with many disease indications. Thus, the kinome targets account for a significant portion of drug discovery efforts. Kinase inhibitor discovery is a very active area as developers explore more deeply into designing immune-modulatory agents as single or combination therapies, tackling chronic disease indications such as inflammation and CNS disorders as well as effectively harnessing allosteric modulators and covalently binding compounds. This year we'll also be discussing PROTACs and the role of artificial intelligence in kinase inhibitor discovery.

Lead Generation Strategies September 17-18, 2019 Boston, MA Program  Finding new chemical entities with high drug potential as fast as possible has always been the goal in early drug discovery. Often the process is separated into two steps: ‘hit’ generation which focuses on quickly finding large numbers of compounds with questionable drug potential followed by secondary screens to reveal promising, high-drug potential leads. Recently though the two processes are often combined because of automation and biophysical advances that enable smaller numbers but higher quality drug leads to be found from the start.

ligand: Pharmaceutical biology  

ligand gated ion channels: A subclass of ion channels that open or close in response to the binding of specific LIGANDS. MeSH 2011

macrocycle: Cyclic macromolecule or a macromolecular cyclic portion of a macromolecule. Note 1: A cyclic macromolecule has no end-groups but may nevertheless be regarded as a chain. Note 2: In the literature, the term macrocycle is sometimes used for molecules of low relative molecular mass that would not be considered macromolecules. IUPAC. Compendium of Polymer Terminology and Nomenclature, IUPAC Recommendations 2008 (the “Purple Book”) (PDF). RSC Publishing, Cambridge, UK

macrocyclics: Constrained Peptides and Macrocyclics September 26-27, 2018 Boston, MA Program |  Macrocyclics covers the progress and challenges of accessing new chemical space – the middle space – to find molecules with drug potential that are bigger than small molecules but smaller than biologics. The hope is that these middle-sized molecules are big enough for more specific interactions with protein-protein interaction surfaces but small enough to penetrate the cell, reach intracellular drug targets and be orally bioavailable. However, theory is still meeting practice. Researchers continue to refine the ’rules’ and properties for the best design of this class of molecules which mainly consist of constrained peptides and synthetic macrocyclics.

Macrocyclics & Constrained Peptides Cell-Penetrating, Bigger Molecules for Oral-Based Therapeutics APRIL 10-11, 2019 San Diego CA Synthetic macrocyclics and constrained peptides are of growing interest in the pharmaceutical industry because they are expanding the chemical space that can be explored for new therapies. This new class is considered ‘ideal’ because its medium size and ring structure are supposed to combine the best properties of biologics and small molecules. They are small enough to get in cells but large enough for specific interactions with more targets such as protein-protein interactions (PPIs) and their cyclic nature enhances their solubility. Some compounds are advancing in clinical trials. However, challenges still remain such as solubility and cell-penetration. Medicinal chemists continue to refine design ideas. Directed-evolution approaches to create libraries based on macrocyclics are also being applied.

membrane proteins: Antibodies Against Membrane Protein Targets-Part 1 September 17-18, 2019 Boston, MA Program |  Antibodies Against Membrane Protein Targets-Part 2 September 18-19, 2019 Boston, MA Program | As the pharmaceutical and biotech industries increasingly shift attention to biologics, much more attention is being paid to the prospect of membrane-bound proteins as drug targets for antibodies and other protein scaffolds. For the large GPCR and ion channel target classes, biologics offer improved selectivity, an alternative for targets with known function that have not been amenable to small molecule drugs and the potential for using antibodies for the targeted delivery of therapeutics. However, for the field to advance, fundamental challenges in optimizing antigen quality and presentation, discovery methodologies, protein engineering and target identification must be resolved.  

Although all membrane proteins are located at the membrane, they otherwise are both structurally and functionally diverse. As we noted in Chapter 2 and discuss in more detail in Chapter 5, every biological membrane has the same basic phospholipid bilayer structure. Associated with each membrane is a set of membrane proteins that enables the membrane to carry out its distinctive activities (Figure 3-32). The complement of proteins attached to a membrane varies depending on cell type and subcellular location.  Some proteins are bound only to the membrane surface, whereas others have one region buried within the membrane and domains on one or both sides of it. Protein domains on the extracellular membrane surface are generally involved in cell-cell signaling or interactions. Domains within the membrane, particularly those that form channels and pores, move molecules across the membrane. Domains lying along the cytosolic face of the membrane have a wide range of functions, from anchoring cytoskeletal proteins to the membrane to triggering intracellular signaling pathways. In many cases, the function of a membrane protein and the topology of its polypeptide chain in the membrane can be predicted based on its homology with another, well-characterized protein.  Membrane proteins can be classified into two broad categories—integral (intrinsic) and peripheral (extrinsic)—based on the nature of the membrane-protein interactions (see Figure 3-32). Most biomembranes contain both types of membrane proteins.  Molecular Cell Biology 4th ed. Membrane Proteins

Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane- associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. MeSH, 1977   Narrower terms: integral proteins, intrinsic proteins, membrane transport proteins, peripheral proteins extrinsic proteins,  
G-protein-coupled receptors GPCRs;   See also GPCRs and Membrane Proteins  Related terms: Microarray categories membrane microarrays,  membrane proteomics

membrane proteomics: Membrane proteins perform some of the most important functions in the cell, including the regulation of cell signaling through surface receptors, cell-cell interactions, and the intracellular compartmentalization of organelles. Recent developments in proteomic strategies have focused on the inclusion of membrane proteins in high-throughput analyses. While slow and steady progress continues to be made in gel-based technologies, significant advances have been reported in non-gel shotgun methods using liquid chromatography coupled to mass spectrometry (LC/MS).  Wu CC, Yates John R,  The application of mass spectrometry to membrane proteomics Nature Biotechnology 21(3): 262- 267, March 2003  Related terms: membrane proteins, membranomics

microbiome: Targeting the Microbiome September 27-28, 2018 Boston, MA Program |    Basic and applied biomedical research from the Human Microbiome Project and other independent studies prove that a disruption of a stable microbiome ecosystem results in dysbiosis. This imbalance leads to chronic disease and health conditions. There is great promise in correlating the microbiome compositions with these diseases and using the microbiome as a tool for therapeutic development.  See also microbiome -Omes & -omics

molecular drug targets: Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Current Drug Targets scope note, Bentham Science  See also molecular targets  

Molecular Pharmacopeia 2006 
For the past decade, the number of molecular targets for approved drugs has been debated. However, if we are to develop predictive methods to identify potential new drug targets, it is important that we establish with confidence the number, characteristics and biological diversity of targets of approved drugs.

molecular profiling: Elsevier  See also Expression gene & protein

molecular targeted therapy: Treatments with drugs which interact with or block synthesis of specific cellular components characteristic of the individual's disease in order to stop or interrupt the specific biochemical dysfunction involved in progression of the disease. MeSH 2011

molecular targets:  Molecular targets are cellular or tissue structures that are intended to be visualized by means of molecular imaging. Different biological structures can potentially serve as imaging targets, ranging from proteins to DNA and RNA.  Springer, Molecular targets  See also molecular drug targets   

multi-targeted therapies: Suites of drugs have been developed that can be used in combination to treat complex diseases that have multiple causes involving multiple targets. In addition, it has been found that many successful small-molecule drugs are promiscuous, i.e., they are single drugs that address multiple targets. Related terms: promiscuous drugs, promiscuous inhibitors

NF-kappa B: Ubiquitous, inducible, nuclear transcriptional activator that binds to enhancer elements in many different cell types and is activated by pathogenic stimuli. The NF-kappa B complex is a heterodimer composed of two DNA- binding subunits: NF-kappa B1 and relA. MeSH, 1991  
Nature News nf-kappaB   Related terms: cytokines 

nuclear hormone receptor proteins: form a class of ligand activated proteins that, when bound to specific sequences of DNA serve as on-off switches for transcription within the cell nucleus. These switches control the development and differentiation of skin, bone and behavioral centers in the brain, as well as the continual regulation of reproductive tissues. Univ of Illinois Urbana Champaign  Theoretical and Computational Bio Physics, Nuclear Hormone Receptors

nuclear receptors: Nuclear receptors are a super family of intra-cellular receptors present in most animal species. They mediate the transcriptional responses to metabolic ligands. In humans, 48 nuclear receptors have been identified. These are characterized as belonging to one of 11 subgroups. The most active targets are the estrogen receptors, glucocorticoid receptors, and progesterone receptors. See also orphan nuclear receptors, cytoplasmic and nuclear receptors

orphan G-protein-coupled receptors: GPCRs with unknown function.

orphan nuclear receptors: A broad category of receptor-like proteins that may play a role in transcriptional-regulation in the CELL NUCLEUS. Many of these proteins are similar in structure to known NUCLEAR RECEPTORS but appear to lack a functional ligand-binding domain, while in other cases the specific ligands have yet to be identified. MeSH 2010

PROTACS  Proteolysis-targeting chimeric molecules: Sept 2019 Boston MA a group of engineered hetero-bifunctional chemical entities that bind to the target and ligase to mediate ubiquitination and subsequent protein degradation. Like PROTACs, other chemical entities and molecular glues, using varied mechanisms-of-action, are being developed to trigger targeted protein degradation. These approaches have a lot of potential in seeking out previously “undruggable” protein targets for applications in drug discovery and for developing new therapeutic modalities. However, some challenges do exist in terms of stability, biodistribution and penetration of these molecules in vivo.

protease inhibitors:  Compounds which inhibit or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES) MeSH 1979

Proteases constitute one of the largest potential drug target enzyme families, with 647 human gene products incorporating protease sequences and mutated proteases having been identified.  In addition, there are many more proteases found in viruses, bacteria, and parasites, which are also potential drug targets. The therapeutic promise of protease inhibitors has been most clearly demonstrated by angiotensin-converting enzyme (ACE) and HIV drugs. 

protein families, protein structure: Protein structure  Critical to determining whether a drug target is druggable

protein kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC  MeSH, 1980  Broader term: kinases Narrower terms: kinase inhibitors; -Omes & -omics kinome,  kinomics

protein kinase inhibitors: Agents that inhibit PROTEIN KINASES. MeSH 2005
Protein kinase evolution, SUGEN, 2012

Protein-Protein Interactions Targeting PPIs and Nucleic Acid Complexes for Therapeutic Interventions APRIL 9-10, 2019 San Diego CA Modulating disease-relevant protein-protein interactions (PPIs) or protein-nucleic acid complexes by chemical agents is a strategy for discovering new compounds with therapeutic potential. However intracellular PPIs are harder to rationally design drugs against or screen in a traditional high-throughput biochemical assay than are traditional intracellular targets such as enzymes. PPIs lack an active site to target. Nevertheless, PPI-targeted drug discovery is moving forward. In fact, the first PPI-targeted drug (against the BCL2 complex) was launched a few years ago for cancer and a few more PPIs are the targets of drug candidates in clinical development.

Disease-relevant intracellular protein-protein interactions occurring at defined cellular sites possess great potential as drug targets. They permit highly specific pharmacological interference with defined cellular functions. Drugs targeting such interactions are likely to act with fewer side effects than conventional medication influencing whole cell functions.  Protein-Protein Interactions as New Drug Targets Series: Handbook of Experimental Pharmacology, Vol. 186 Klussmann, Enno; Scott, John (Eds.) Springer 2008

A central phenomenon determining the biological pathways found in living systems.  They are the focus of many proteomic technologies being developed today to decipher an intricate network of interactions. Correlated changes in protein expression (such as co- regulation or sequential regulation) provide a hint that two proteins may be interacting with each other. Play a major role in almost all relevant physiological processes occurring in living organisms, including DNA replication and transcription, RNA splicing, protein biosynthesis, and signal transduction.   Related terms: Proteomics  interaction proteomics, yeast two-hybrid.

receptors, cytoplasmic and nuclear: Proteins in the cytoplasm or nucleus that specifically bind signaling molecules and trigger changes which influence the behavior of cells. The major groups are the steroid hormone receptors (RECEPTORS, STEROID), which usually are found in the cytoplasm, and the thyroid hormone receptors (RECEPTORS, THYROID HORMONE), which usually are found in the nucleus. Receptors, unlike enzymes, generally do not catalyze chemical changes in their ligands. MeSH 1994   See also nuclear hormone receptors 

receptor tyrosine kinase like orphan receptors: A family of cell surface receptors that were originally identified by their structural homology to neurotropic TYROSINE KINASES and referred to as orphan receptors because the associated ligand and signaling pathways were unknown. Evidence for the functionality of these proteins has been established by experiments showing that disruption of the orphan receptor genes results in developmental defects. MeSH 2010 

retargeting: A conceptual breakthrough in gene therapy would be gene transfer vector that could be systemically applied, allowing targeted gene transfer into a predetermined cell type.  C. Haynes et. al, Modified envelope glycoproteins to retarget retroviral vectors, Current Gene Therapy 3(5): 405- 410, Oct. 2003  Related term: Biologics gene therapy

RNA as a drug target: September 18-19 2019 Boston MA RNA molecules are crucial for delivering cellular information and genetic regulation, but until recently, the drug discovery world has emphasized protein drug targets. Our lack of knowledge in RNA biology prevented us from exploring possibilities of RNA drug targets, but with recent advances in technologies such as sequencing, new therapeutic strategies are being explored.

target: Molecules in the body that may be addressed by drugs to produce a therapeutic effect. (Also used to refer to the material -- DNA or RNA - that one exposes to the probes on a microarray so that hybridization can be measured subsequently. A molecule that may interact with a drug or drug candidate. Pharmaceutical industry expert Jürgen Drews (now chairman of International Biomedicine Management Partners, Inc. and formerly of Hoffman La Roche) has noted that all drug therapy is currently based on 500 molecular targets.

Target in a drug screening context often means drug target. See also target (hybridization). Narrower terms: disease targets, gene target, tractable targetsRelated terms: drug targeting,  target validation

target amplification: Increasing the amount of target nucleic acid, providing more template for the label, to achieve improved detection. Useful for low levels of expression or abundance or very small sample sizes. Target amplification increases the amount of target nucleic acid, providing more template for the label and therefore more signal. This approach helps overcome problems associated with low expression of some genes or small sample sizes. The kinetics of the amplification step, however, must be reproduced exactly in these approaches; otherwise, changes observed on the array could be the result of differential amplification. Target- amplification processes include PCR, Rolling Circle Amplification RCA, Strand Displacement Amplification SDA.  Related terms: Gene amplification & PCR

target characterization: Requires evidence that the potential target actually plays a role in the disease process, and that modulation of the target may ameliorate or reverse a disease phenotype. A potential target which may be a validated target. Related terms:  target identification, target qualification, target validation  

target engagement Determining the biological functions of proteins requires selective tools to perturb their expression and/or activity in living systems. Molecular biology methods, such as targeted gene disruption and RNA interference, are ubiquitous and fairly straightforward methods to achieve this goal. Small-molecule probes offer complementary and, in some ways, superior tools for interrogating proteins and pathways because they can provide greater spatiotemporal control over protein function and can perturb this parameter without concomitant changes in protein expression1. This latter feature, of course, also means that the effect of small-molecules on protein function can rarely be inferred from simple protein abundance measurements like Western blotting. Alternative assays must be enlisted to confirm that a small molecule interacts with its intended protein target in a living system, a parameter that is referred to as target engagement.  Why is measuring target engagement important? Researchers in the pharmaceutical industry and academic medicine have long recognized the value of proximal biomarkers that can faithfully report on drug-target interactions in preclinical and clinical settings2-5. Biomarkers enable a direct correlation between target engagement and measurements of drug efficacy and/or toxicity. If, for instance, full target occupancy is confirmed for a drug in vivo and the drug fails to produce an expected therapeutic effect, then the target and mechanism were properly tested and invalidated for the intended clinical indication. Absent measurements of target engagement, however, it can be very difficult to discern the basis for a drug's lack of efficacy6. Was the target invalid or did the drug fail to fully engage the target in vivo? An ideal assay would also measure: 1) the extent of target engagement, which can help to determine drug doses that produce efficacy at fractional target occupancy, while limiting side effects that might be caused by complete target occupancy; and 2) the potential for drug interactions with off-target proteins, such that efficacy and toxicity can be correlated with drug selectivity in vivo.  Simon GM, Niphakis MJ, Cravatt BF. Determining target engagement in living systems. Nature chemical biology. 2013;9(4):200-205. doi:10.1038/nchembio.1211.

target evaluation:
Can cover the range of target- winnowing strategies, from target identification to target validation.   

target families/target family:  The majority of pharmaceutically relevant drug targets cluster into densely populated target families, thus offering a novel approach that complements the currently favoured screening paradigm in medicinal chemistry. This approach uses a privileged structure concept whereby molecular masterkeys are developed that account for a target family wide structural or functional commonality. Numerous lead compounds, based on multipurpose privileged structures, can be generated that address a variety of targets from a gene family of interest, irrespective of therapeutic area. Medicinal  chemistry of targeted directed masterkeys, Drug Discovery Today, 2003 

Although the sheer numbers of potential targets uncovered through genomics- based methods create an enormous need for target- identification and validation technologies, these numbers also make possible new opportunities, which go way beyond what is possible via traditional drug discovery methods. The limited number of target families addressed by traditional drug discovery methods suggests that these methods are "boxed in" and unable to create the numbers of novel drugs (three to five per year for major companies) that will be necessary to meet pharmaceutical companies' business goals. 

target glut:  While an individual company may have four or five times as many targets under analysis now than it did five years ago, most of those targets are completely new or poorly understood. Lack of annotation for genomic data is a major problem in choosing the best targets to pursue for drug developmentRelated terms:  target identification, target screening, target validation; Bioinformatics: information overload; Drug discovery & development druggable genome

target haplotype: Pharmacogenomics

target hopping: Directed crossover of a compound to a new target. "Chemical genomics advances drug discovery" Genetic Engineering News 22 (13):1 , July 2002   Related terms:  Assays lead hopping  Chemistry scaffold hopping 

target (hybridization): 
There are currently at least two nomenclature systems for referring to hybridization partners. Both use common terms ‘probes’ and ‘targets’ … With respect to the nucleic acids whose entwining represents the hybridization reaction, the identify of one is defined - it tends to be tethered to the solid phase, making up the microarray itself. The identity of the other is revealed by hybridization. The strategy of the ‘standard’ microarray therefore parallels that of a reverse dot- blot, in which the probe is immobilized. For this reason, authors of articles appearing in this supplement have been encouraged to describe the tethered nucleic acid as ‘probe’ and the free nucleic acid as ‘target’. Chipping Forecast supplement "A note on nomenclature" Nature Genetics 21 (1s): 1 Jan 1999 Has this been standardized yet?  See also the note under probes- microarray Microarrays

A molecule (usually a protein gene product, but sometimes a DNA sequence, or, in the case of antisense drugs, an mRNA) that may interact with a drug or drug candidate.  Instead of target, some people use sample [in the context of microarrays] . We find fault with this usage, though we fall into it occasionally, because the same word often refers to the biological material from which mRNA was extracted (e.g., tissue or serum from patients or laboratory animals). In addition, sample is an important term in statistics, where it has a completely different meaning. (It means the subset of a population that is surveyed for the purpose of estimating properties of the entire population.). 
See also target
[above] Related terms: Drug discovery & development Sample and sample preparation 

target identification:   Target Identification & Validation-Part 1 September 26-27, 2018 Boston, MA Program |  Finding novel, druggable targets for therapeutic intervention remains a top priority for the pharma/biotech industry, especially when it comes to building a robust drug discovery pipeline. It also remains a formidable challenge and companies continue to invest a lot of time and resources in identifying and validating good drug targets to pursue. What are the challenges in target discovery? What tools and strategies are being used and how well are they working? What’s being done to ensure that validated targets lead to better and safer therapies? 

Target Identification & Validation-Part 2 September 27-28, 2018 Boston, MA Program | This part of the Target Identification and Validation conference will describe how phenotypic screening and chemical biology can be used to find new drug targets, validate existing targets for new indications, and better understand how inhibiting or activating these targets could impact other cellular pathways.

the process of identifying the direct molecular target – for example protein or nucleic acid – of a small molecule. In clinical pharmacology, target identification is aimed at finding the efficacy target of a drug/pharmaceutical or other xenobiotic. The techniques used may be based on principles of biochemistry, biophysics, genetics, chemical biology or other disciplines. Nature: target identification

Target identification of biologically active molecules such as natural products, synthetic small molecules, peptides, and oligonucleotides mainly relies on affinity chromatography, activity-based probes, or photoaffinity labeling (PAL). Amongst them, activity-based probes and PAL have offered great advantages in target identification technology due to their ability to form covalent bonds with the corresponding targets. Activity-based probe technology mainly relies on the chemical reactivity of the target proteins, thereby limiting the majority of the biological targets to enzymes or proteins which display reactive residues at the probe-binding site. Molecules 2013, 18(9), 10425- 10451;  doi: 10.3390/molecules180910425 Review  Recent Advances in Target Characterization and Identification by Photoaffinity Probes Jitapa Sumranjit 1,2 and Sang J. Chung

Identifying molecules that clearly play a role in a disease process. Target identification methods  provide a finer degree of detail than target screening and require evidence that the gene/ protein is correlated with the disease.   

target labelling: Targets for arrays are labelled representations of cellular mRNA pools. Typically reverse transcription from an oligo-dT primer is used … Frequently total RNA pools (rather than mRNA selected on oligo-dT) are labelled, to maximize the amount of message that can be obtained from a given amount of tissue.  DJ Duggan et al “Expression profiling using cDNA microarrays” Nature Genetics 21(1s): 10- 14, Jan 1999  

target molecules: Target genes or target proteins.  

target prioritization:  Drug target prioritization by perturbed gene expression and network information ,2015

target prioritization TDR database The TDR Targets project seeks to exploit the availability of diverse datasets to facilitate the identification and prioritization of drugs and drug targets in neglected disease pathogens.

target proteins: 
The project TargId at GMD SCAI focuses on methods to address the arguably most urgent problem: the elucidation of the origins and mechanisms of human diseases, culminating in the identification of potential drug target proteins. Identification of Drug Target Proteins, by Alexander Zien, Robert Küffner, Theo Mevissen, Ralf Zimmer and Thomas Lengauer ERCIM News No.43 - October 2000 

target qualification:
Qualifying that potential target genes or proteins clearly have a role in a disease process.

target selection: The main purpose of the Bioinformatics Core (BIC) is to select the target for research. The goals of BIC are to develop complete high throughput technology for structural genomics beginning with high throughput computational selection of target proteins, followed by robotic expression and crystallization and fully automated data collection and structure solution. List of Important Definitions, JCSG Joint Center for Structural Genomics    

target validation:  The identification and validation of disease-causing target genes is an essential first step in drug discovery and development. Genomics and proteomics technologies have already begun to uncover novel functional pathways and therapeutic targets in several human diseases such as cancers and autoimmunity. Also, bioinformatics approaches have highlighted several key targets and functional networks. In contrast to gene-profiling approaches, phenotype-oriented target identification allows direct link between the genetic alterations and a disease phenotype. Therefore, identified genes are more likely to be a cause rather than a consequence of the disease. Once a gene target or a mechanistic pathway is identified, the next step is to demonstrate that it does play a critical role in disease initiation, perpetuation, or both. Methods Mol Biol. 2007;360:1-12. Main approaches to target discovery and validation. Sioud M

Target validation involves demonstrating that a molecular target is critically involved in a disease process, and that modulation of the target is likely to have a therapeutic effect. Determining which among genes or proteins being investigated as potential drug targets lead to phenotypic changes when modulated, suggesting that they may have value as therapeutic targets. Many people would say a target is truly validated only after proven effective in human trials.  The definition of target validation is clearly evolving, can be seen as "slippery" and means different things to different people.  

target validation technologies: A range of strategies exists for modulating gene expression in vitro and in vivo. These strategies include the use of antibodies, negative dominant controls, antisense oligonucleotides, ribozymes, and small-interfering RNAs. In contrast to in vitro assays, mouse reverse genetics such as knockout phenotypes has become a powerful approach for deciphering gene function and target validation in the context of mammalian physiology. In addition to disease-causing genes, the identification of antigens that stimulate both arms of the immune system is the major goal for effective vaccine development.  Methods Mol Biol. 2007;360:1-12. Main approaches to target discovery and validation. Sioud M

A number of technologies including downregulation of gene expression (gene knockdown, antisense, ribozymes and zinc finger proteins), protein inhibition (phage libraries and antibodies), cellular assays, chemical genetics, and combinatorial biology are linked with target validation. The integration of various technologies is another challenge.

targeted gene repair: A technique which uses synthetic oligonucleotides to direct the cell's inherent DNA repair system to correct a mutation at a specific site in an episome or chromosome.
MeSH 2007

targeted therapy:  A type of treatment that uses drugs or other substances to identify and attack specific types of cancer cells with less harm to normal cells. Some targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells. Other types of targeted therapies help the immune system kill cancer cells or deliver toxic substances directly to cancer cells and kill them. Targeted therapy may have fewer side effects than other types of cancer treatment. Most targeted therapies are either small molecule drugs or monoclonal antibodies.  NCI  Dictionary of cancer terms

The goal of targeted therapeutics is to create drugs that by the specificity of their design and delivery will make them more effective in treating disease and less toxic.

Therapeutic Targets Database: 
National University of Singapore

tractable targets:  Targets from families such as 7TM receptors, ion channels, kinases and proteases which have produced previous hits.  Martin J. Valler,  Darren Green  "Diversity screening versus focussed screening in drug discovery " Drug Discovery Today 5(7): July 2000  Related terms: druggable, low hanging fruits, pharmaceutically tractable 

ubiquitin [as a drug target]: Screening for ubiquitin ligase substrates: Identification of E3 ligase substrates is critical to understand its implication in human diseases since deregulation of E3-substrate interactions are often served as major cause in many. To overcome the limitation of mechanism used to identify the substrates of the E3 Ubiquitin Ligase, a system called the 'Global Protein Stability (GPS) Profiling' was developed in 2008.[112] This high-throughput system made use of reporter proteins fused with thousands of potential substrates independently. By inhibition of the ligase activity (through the making of Cul1 dominant negative thus renders ubiquitination not to occur), increased reporter activity shows that the identified substrates are being accumulated. This approach added a large number of new substrates to the list of E3 ligase substrates….Finding a specific molecule that selectively inhibits the activity of a certain E3 ligase and/or the protein-protein interactions implicated in the disease remains as one of the important and expanding research area. Moreover, as ubiquitination is a multi-step process with various players and intermediate forms, consideration of the much complex interactions between components needs to be taken heavily into account while designing the small molecule inhibitors.[97]   Wikipedia accessed  2018 Nov 5

ubiquitin:  Emerging ubiquiting & autophagy targets September 17-18 2019 Boston, MA  Autophagy and the ubiquitin-proteasome system (UPS) are the two major pathways responsible for protein degradation and maintenance of cellular homeostasis. They consist of well-controlled, selective mechanisms for intracellular protein degradation and turnover. New understanding of the role and molecular mechanisms involved in the dysregulation of autophagy and ubiquitin pathways has revealed its underlying role in cancer, CNS, immunology and other diseases. However, the diversity of substrates and the multi-step processes involved, make it difficult to target these pathways for therapeutic intervention. In recent years, the development of high-quality chemical probes, small molecule modulators, assays and screening platforms have helped identify novel autophagy and ubiquitin targets for drug discovery. 

ubiquitin proteosome system: Targeting the Ubiquitin-Proteasome System Novel Tools and Compounds to Modulate DUBs, Ligases and Other Proteins APRIL 10-11, 2019 SAN Diego CA The ubiquitin-proteasome system (UPS) is a complex, highly regulated network of proteins that is responsible for intracellular protein degradation and turnover. Advances in our understanding of the role and molecular mechanisms of the UPS components in disease and the development of high quality chemical tools and inhibitors have turned the previously “undruggable” UPS targets into an exciting opportunity for small molecule drug intervention. Over the past years, we have seen the development of a new generation of deubiquitinating enzymes (DUBs) and proteasome inhibitors poised for clinical development, as well as the discovery of novel inhibitors for disrupting the protein-protein interactions in ligases and hijacking the UPS for targeted protein degradation.

undruggable targets: Only 2% of human proteins interact with currently approved drugs. Furthermore, it is estimated that only 10-15% of human proteins are disease modifying while only 10-15% are druggable (there is no correlation between the two), meaning that only between 1-2.25% of disease modifying proteins are likely to be druggable. Hence it appears that the number of new undiscovered drug targets is very limited.[20][21][22]

A potentially much larger percentage of proteins could be made druggable if protein–protein interactions could be disrupted by small molecules. However the majority of these interactions occur between relatively flat surfaces of the interacting protein partners and it is very difficult for small molecules to bind with high affinity to these surfaces.[23][24] Hence these types of binding sites on proteins are generally thought to be undruggable but there has been some progress (by 2009) targeting these sites.[25][26]    Wikipedia accessed 2019 June 24

virtual target screening: Computational methods involving virtual screening could potentially be employed to discover new biomolecular targets for an individual molecule of interest (MOI). However, existing scoring functions may not accurately differentiate proteins to which the MOI binds from a larger set of macromolecules in a protein structural database. An MOI will most likely have varying degrees of predicted binding affinities to many protein targets. However, correctly interpreting a docking score as a hit for the MOI docked to any individual protein can be problematic. In our method, which we term "Virtual Target Screening (VTS)", a set of small drug-like molecules are docked against each structure in the protein library to produce benchmark statistics. This calibration provides a reference for each protein so that hits can be identified for an MOI. VTS can then be used as tool for: drug repositioning (repurposing), specificity and toxicity testing, identifying potential metabolites, probing protein structures for allosteric sites, and testing focused libraries (collection of MOIs with similar chemotypes) for selectivity. J Chem Inf Model. 2012 Aug 27;52(8):2192-203. doi: 10.1021/ci300073m. Epub 2012 Jul 23. Virtual target screening: validation using kinase inhibitors. Santiago DNPevzner YDurand AATran MScheerer RRDaniel KSung SSWoodcock HLGuida WCBrooks WH

Drug targets resources
Harding SD, Sharman JL, Faccenda E, Southan C, Pawson AJ, Ireland S, Gray AJG, Bruce L, Alexander SPH, Anderton S, Bryant C, Davenport AP, Doerig C, Fabbro D, Levi-Schaffer F, Spedding M, Davies JA; NC-IUPHAR. (2018) 
The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGYNucl. Acids Res. 46 (Issue D1): D1091-D1106. doi: 10.1093/nar/gkx112   An expert-driven guide to pharmacological targets and the substances that act on them. Glossary

Royal Society of Chemistry, Drug and target mapping 

Drug targets Conferences 
Discovery on Target

Drug targets CDs, DVDs 
Drug targets Short courses 

How to look for other unfamiliar  terms

IUPAC definitions are reprinted with the permission of the International Union of Pure and Applied Chemistry.

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