The true test of validation comes only when a selective inhibitor for the chosen target is advanced to the clinic and shown to be efficacious in the appropriate human disease. However, advancing the wrong target to this stage is a costly mistake. Much of the impact of genomics on drug development thus far has been focused on the identification and validation of biological targets. While much of this research on targets is based only on comparisons of the biology of health and disease, sooner or later it becomes critical to integrate the activity of chemical compounds with the body.

Drug discovery term index: Guide to terms in these glossaries    Site Map  Related glossaries include: Applications Drug discovery & development   Molecular Diagnostics
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allosteric modulators: Allosteric modulation, while an old theory in enzyme kinetics, has taken off recently in applications to the drug discovery arena, especially where G Protein-Coupled Receptors (GPCRs) are involved. Not only can allosteric modulators be developed as drugs that can activate specific functions of a GPCR or other target, thereby potentially reducing side-effects due to non-selective G protein coupling or signaling, but they can be used as tools in drug discovery to decipher the signaling complexities of a GPCR.  Allosteric Modulators November 3-4, 2011 • Boston, MA Program | Register | Download Brochure 

binding, competitive: The interaction of two or more substrates or ligands with the same binding site. The displacement of one by the other is used in quantitative and selective affinity measurements. MeSH 1973

binding site: A specific region (or atom) in a molecular entity that is capable of entering into a stabilizing interaction with another molecular entity. IUPAC Bioinorganic

The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. MeSH, 1968 Related terms: ligand; receptor mapping. Narrower term: binding sites, antibody 

binding sites, antibody: Local surface sites on antibodies which react with antigen determinant sites on antigens. They are formed from parts of the variable regions of the Fab fragment of the immunoglobulin. MeSH, 1973

BioIT World Weekly Update: Drug & disease targets http://www.bio-itworldweekly.com/category/5/drug-disease-targets/ 

biological target A biological target is a biopolymer such as a protein or nucleic acid whose activity can be modified by an external stimulus. accessed Jan 10, 2011 en.wikipedia.org/wiki/Drug_target

Biomarker Breakthroughs: drug targets http://www.biomarkerbreakthroughs.com/category/80/drug-targets/ 

cancer cell metabolism: The fact that cancer cells have an altered glucose metabolism, has sparked new interested in the pharmaceutical industry in it’s continuous quest of finding new ways to target tumors. Reversing the increased glucose consumption in cancer cells is an important step and has great potential for therapeutic drug developments. Cancer Metabolism as a Drug Target November 2-3, 2011 • Boston, MA Program | Register | Download Brochure


channel blocker,  Compound that reduces or eliminates the conductance of an ion channel by impeding the movement of ions through that channel  IUPAC Biomolecular Screening

chemical ligand studies: Use a more general set of compounds [than chemical genomics] (often from combinatorial libraries) to find new targets. Once the new targets are found, more specific assays are done. In other words, with the chemical ligands approach, one does blind screening of chemical libraries using cellular assays. When one gets an interesting biological effect, one uses the compound to find the target it modulates. [The precise definition of the following terms varies widely between drug discovery companies. The meanings given here are aligned with the use of the terms within the lead discovery function at GlaxoWellcome.  Martin J. Valler,  Darren Green  "Diversity screening versus focussed screening in drug discovery" Drug Discovery Today 5(7): July 2000 

chemogenomics:  British Journal of Pharmacology, 2007 http://www.nature.com/bjp/journal/v152/n1/full/0707308a.html 

compound profiling: Biology has considerable experience with gene and protein- centered informatics, but chemistry is at an earlier stage of developing databases that are truly compound- centric. The historical paradigm of identifying and optimizing hits for potency, and then looking to evaluate and optimize for ADME and toxicity properties is quickly shifting to a more parallel approach that considers ADME/Tox properties at an earlier stage. This concept is epitomized by methods for differentiating between drug- like and non- drug- like compounds, the use of which is increasing significantly. Moving compound profiling earlier means that many more compounds must be assessed, which is both the value and the challenge of this shift.  http://www.healthtech.com/Conferences/2007/cpf/index.asp 

compound validation: Assays & screening

cytokine-based therapeutics: Cytokines have drawn immense interest from the pharmaceutical industry over the last two decades. Great effort has been devoted to finding ways to reproduce their effects—or to block their activity—in the quest to create novel drugs for cancer, infectious diseases, inflammatory and immune disorders, and myelosuppression. insight Pharma Reports Cytokine Therapeutics: A Vibrant Pipeline and Active Approved Market Full Report | Executive Summary  2007    Related term: Protein categories: cytokines 

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

deorphanize: Identification of new ligands for receptors.

Discovery on Target  November 2-4, 2011 • Boston, MA  Program | Register | Download Brochure  
 

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  Google = about 3,250, Aug, 24, 2002; about 12,900 June 10, 2004; about 104,000 Nov 13, 2006, about 41,900 June 25, 2009

drug leads: small molecule ligands  DS Wishart Identifying putative drug targets and potential drug leads: starting points for virtual screening and docking. Methods Mol Biol. 2008;443:333-51.

drug receptors: Proteins that bind specific drugs with high affinity and trigger intracellular changes influencing the behavior of cells. Drug receptors are generally thought to be receptors for some endogenous substance not otherwise specified.  MeSH, 1968  Broader term: receptors

drug target, drug targets:  A defined molecule or structure within the organism, which is linked to a particular disease. For disease intervention, the drug target may either blocked/inhibited or activated by a drug (small organic molecules, antibodies, therapeutic proteins).  Cytos Biotechnology AG Glossary of Biological Terms http://www.cytos.com/?id=197 

A protein or protein complex which is implicated in a disease and so has the potential to be affected by a specific drug. Membrane Protein Structure Initiative Glossary www.mpsi.ac.uk:8080/pims/help/glossary.html

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, targets  Google "drug target" = about 10,700, Aug, 24, 2002; about 16,500 June 16, 2003; about 33,500 June 10, 2004; about 586,000 Nov 13, 2006, about 513,000 Aug 18, 2008 [typo in 2006?]
How many drug targets are there? John P Overington, et. al, Nature Reviews Drug Discovery, 2006 http://www.nature.com/nrd/journal/v5/n12/pdf/nrd2199.pdf 

drug targeting:  A strategy aiming at the delivery of a compound to a particular tissue of the body. IUPAC Medicinal Chemistry  Related terms: target, target validation. Narrower terms: gene target, protein target   Google = about  6,150, Aug, 24, 2002; about 15,200 June 10, 2004; about 295,000 Nov 13, 2006

druggable targets: "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 . http://www.nature.com/horizon/chemicalspace/highlights/s3_nonspec2.html

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 http://www.nature.com/nrd/journal/v5/n12/pdf/nrd2199.pdf 

emerging targets: The report assesses the issues in target-based drug discovery and development as well as several specific issues that are common to these and other complex diseases with high unmet medical need. … Evaluation of leading emerging targets in terms of signaling pathways and therapeutic strategies. Insight Pharma Reports Emerging Targets in Disease with High Unmet Needs, 2006

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  Google = about  1,080, Aug, 24, 2002; about 4,070 May 12, 2004; about 96,900 Nov 13, 2006. about 1,110,000 Jan 10, 2011

G-protein-coupled receptors GPCRs: Today’s drug discovery around G protein-coupled receptors (GPCRs) is quite different from decades ago, when GPCRs weren’t even known to be the target of the newest drugs on the market. Are today’s knowledge-based drug discovery approaches better and faster though? Join your scientific colleagues for this day and a half meeting to debate these questions and more. Learn how the latest functional screening strategies and cutting-edge GPCR crystal structures are/can be applied to drug discovery and development. Also hear case studies around drug candidates developed against specific GPCRs and keep abreast of their progress in the clinic and pharmacological challenges.  GPCR-Based Drug Discovery November 2-3, 2011 • Boston, MA Program | Register | Download Brochure

Current advances in functional screening methodologies, medicinal chemistry, and structure-based drug design have generated large increases in the number and diversity of GPCR drug targets. Furthermore, basic research advances have opened the way for still further exploitation of this target class. Insight Pharma Reports, GPCRS: Dawn of a new era? 2008

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

HDAC inhibitors: Histone deacetylases (HDAC) are a promising target for drug intervention and a number of novel and structurally diverse HDAC inhibitors (HDACi) are being tested at both the pre-clinical and clinical stages. Although, being developed mainly as anti-tumor agents for cancer, many HDACi are now being explored for their efficacy in treating CNS, immunologic, metabolic and inflammatory disorders. However, much remains to be elucidated about the biological functions of HDAC in the cell. Studying the functional implications of modulating HDAC and understanding the signaling pathways that govern the mode-of-action of HDACi and their possible adverse cellular effects, is an area of intense research.  Targeting Histone Deacetylases November 2-3, 2011 • Boston, MA Program | Register | Download Brochure


ion channels:  Ion Channels are now established as an important target group for developing pharmaceutical therapeutics. To successfully move forward in this area, many challenges had to be overcome and several strategies are now in place to validate new targets and to improve and generate new leads. New techniques such as high-throughput screening, new patch-clamp methods, new imaging and updated cell based assays are providing information on new structural leads, on selectivity and on mechanism of action, as well as on emerging new therapeutic areas.  
Ion channels as therapeutic targets, Discovery on Target Nov 2010 Boston MA  order CD 

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

Ion Channel Modulator Pipelines  Insight Pharma Reports, September 2009 Table of Contents | Tables and Figures | Executive Summary

kinase inhibitor chemistry: Kinase inhibitors have matured into key targets in drug discovery. They play an important role in cancer therapeutic developments and have recently been established as novel targets for metabolic diseases, pain treatment and CNS therapeutics.  While a lot of knowledge is available about the biology of kinases, what the industry needs now is to explore the chemical space.  More information on the structure, binding sites and binding interaction of kinases is necessary in order to optimize leads and to develop novel inhibitors.
Kinase Inhibitor Chemistry April 13-14, 2011 San Diego CA  

kinase inhibitors: The kinase inhibitor field is maturing. This conference is designed to examine the question of what lays ahead, what is in store for the pharmaceutical industry and what new avenues are opening up in regards to technologies and methods used or in regards to novel targets and therapeutic approaches explored. What novel kinase indications are “out there”, in addition to cancer as a target, what other therapeutic areas are blossoming? Key issues such as addressing resistance, selectivity versus safety, developing lead compounds, integrating chemistry and biology, using promising techniques such as fragment – and structure based design as well as optimizing PK and PD and how to analyze the flood of data available will be addressed. Next-Gen Kinase Inhibitors June 4-6, 2012 • Cambridge, MA Program | Register | Download Brochure  
      

Kinase Inhibitors as drug targets are at the peak of research and development. The pharmaceutical field is now shifting its effort to more non-oncology therapeutic areas. Novel applications for existing inhibitors are being researched and new targets to develop cancer therapeutics are being explored. With over 40% of the projects of large pharma companies in non-oncology areas, there is clearly a need to address the developments and challenges arising. Emerging Targets for the Kinase Pipeline November 2-3, 2011 • Boston, MA Program | Register | Download Brochure


kinase therapeutics: The number of kinase inhibitors entering clinical development has increased significantly in recent years. In addition to major pharmaceutical and biotech companies, an increasing number of emerging companies are focusing on their development. By 2020, small-molecule kinase inhibitors could generate annual revenues > $25 billion. Kinase Therapeutics: Pipeline Assessment and Commercial Prospects January 2010 Related terms:  kinase inhibitors, protein kinases 

ligand: In inorganic chemistry the ligands are the atoms or groups of atoms bound to the central atom (see also coordination). The root of the word is sometimes converted into the verb to ligate, meaning to coordinate as a ligand, and the derived participles, ligating and ligated…In biochemistry the term ligand has been used more widely: if it is possible or convenient to regard part of a polyatomic molecular entity as central, then the atoms or groups or molecules bound to that part may be called ligands. IUPAC Bioinorganic

Pharmacologists traditionally divide ligands into agonists, which stimulate receptors, and antagonists, which bind to receptors and block endogenous mediators. According to the conventional view, the agonist fits into the receptor, like a key fits a car's ignition, switching on the internal machinery. Antagonists fit the ignition, but block endogenous transmitters. But recent studies suggest that many receptors spontaneously activate internal machinery. In these cases, the receptor is more akin to an accelerator. Mark Greener, Driving Changes in Ligand Theory, The Scientist 18(15): 32, Aug. 2, 2004 http://www.the-scientist.com/yr2004/aug/research4_040802.html 

A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) MeSH 1974 

Molecules (e.g., drugs) that bind to active sites on proteins. Particularly used of small molecules that bind to larger molecules. Narrower term: protein ligand; Related terms: antigen, binding site,  enzyme- substrate, hormone- receptor reaction, lock and key  Google = about 301,000 Aug. 13, 2002  about 1, 170,000 Dec. 3, 2003

ligand design: The design of ligands using structural information about the target to which they should bind, often by attempting to maximize the energy of the interaction. IUPAC Computational

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

membrane proteins: Protein categories  Important as drug targets

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 http://www.bentham.org/cdt/index.htm  See also molecular targets  
Google = about  82, Aug, 24, 2002; about 201 June 10, 2004; about 2,060 Nov 13, 2006, about 938 Aug 17, 2008

Molecular Pharmacopeia http://www.nature.com/focus/molecularpharmacopoeia/index.html 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: A dynamic new discipline, capable of generating a global view of mRNA, protein patterns, and DNA alterations in various cell types and disease processes.  MP integrates the expanding genetic databases from the Human Genome Project with newly developed expression analysis technologies and holds great promise to help us: Understand the molecular anatomy of normal cells and cells in various stages of disease.  Develop new diagnostic and therapeutic targets for clinical intervention. Explain the relationship between genotype and phenotype in humans, which is still largely unknown. NCI, NIH CGAP "Molecular Profiling"  http://cgap-mf.nih.gov/index.html  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 targeting: The idea behind molecular targeting is to design drugs that specifically attack the molecular pathways that cause disease, without disrupting the normal functions in our cells and tissues. Drugs developed using this approach can be less toxic and more effective than current medicines. Molecular Targeting, PhRMA, innovation.org http://www.innovation.org/index.cfm/FutureofInnovation/NextWaveofInnovation/Molecular_Targeting

molecular targets:  Collections of genes organized by pathways and by ontology (functional classification) permitting aggregate evaluation of anomalies (overexpression, underexpression, mutation). Molecular Targets, Cancer Molecular Analysis Project, National Cancer Institute http://cmap.nci.nih.gov/Targets   Can include antibodies, enzymes, receptors.  See also molecular drug targets   Google = about 12, 200, Aug. 24, 2002; about 42, 600 June 10, 2004; about 658,000 Nov. 13, 2006; about 832, 000 May 24, 2007

nodal signaling ligands: Members of the transforming growth factor superfamily that play a role in pattern formation and differentiation during the pregastrulation and GASTRULATION stages of chordate development. Several nodal signaling ligands are specifically involved in the genesis of left-right asymmetry during development. The protein group is named after a critical region of the vertebrate embryo PRIMITIVE STREAK referred to as HENSEN'S NODE. MeSH 2009 

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. Some 13% of drugs approved for sale in the United States are nuclear receptors with 15 of these drugs in the top 200 prescribed medicines. These top drugs represented $27.5 billion of sales revenue in 2009. The top-selling drug in this category is GlaxoSmithKline’s drug Advair/Seretide with sales of $7.8 billion in 2009. The major indications for these drugs include asthma, COPD, diabetes type II, hyperlipidemia, contraception, hormone replacement therapy, prostate cancer, and osteoporosis. Clearly nuclear receptors are an important class of targets for pharmaceutical development. Insight Pharma Reports Nuclear Receptors: The Pipeline Outlook  2010 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

orphan receptors: Receptor for which no ligands have yet been identified.  Related terms: deorphan, deorphanize

pharmacophores: The ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target structure and to trigger (or to block) its biological response. Does not represent a real molecule or a real association of functional groups, but a purely abstract concept that accounts for the common molecular interaction capacities of a group of compounds towards their target structure. Can be considered as the largest common denominator shared by a set of active molecules. This definition discards a misuse often found in the medicinal chemistry literature which consists of naming as pharmacophores simple chemical functionalities such as guanidines, sulfonamides or dihydroimidazoles (formerly imidazolines), or typical structural skeletons such as flavones, phenothiazines, prostaglandins or steroids. Pharmacophoric descriptors are used to define a pharmacophore, including H- bonding, hydrophobic and electrostatic interaction sites, defined by atoms, ring centers and virtual points. IUPAC Medicinal Chemistry

The ensemble of steric and electronic factors which are necessary to insure supramolecular interactions with a specific biological target structure. IUPAC Combinatorial Chemistry

A  template of chemical properties for an active site of a protein - representing these properties’ spatial relationship to one another - that theoretically defines a ligand that would bind to that site. 

pharmacophore generation: A procedure to extract the most important common structural  features relevant for a given biological activity from a series of molecules with a similar  mechanism of action. IUPAC Computational

phosphoinositide 3 kinase PI3K:  Phosphoinositide 3-kinases  (PI3K) are important drug targets for developing tumor treatments, due to their involvement with various signaling pathways and cell functions such as cell growth, proliferation, apoptosis and intracellular trafficking and drug resistance. In the last few years, new applications for non-tumor related diseases are also slowly emerging.  Targeting the PI3K Pathway November 3-4, 2011 • Boston, MA Program | Register | Download Brochure  


promiscuous drugs: We contend that an ideal drug may be one whose efficacy is based not on the inhibition of a single target, but rather on the rebalancing of the several proteins or events, that contribute to the etiology, pathogeneses, and progression of diseases, i.e., in effect a promiscuous drug....  Corollaries to this argument are that the growing fervor for researching truly selective drugs may be imprudent when considering the totality of responses; and that the expensive screening techniques used to discover these, may be both medically and financially inefficient. Promiscuous drugs compared to selective drugs (promiscuity can be a virtue) Simon K Mencher and Long G Wang, BMC Clinical Pharmacology 2005, 5:3 doi:10.1186/1472-6904-5-3 http://www.biomedcentral.com/1472-6904/5/3/abstract  Related term: selectivity

promiscuous inhibitors: Nonspecific, seem to be hits in multiple high- throughput screening (HTS)  campaigns, but which turn out to be dead ends when attempts are made to optimise their activity, a key problem in the field of HTS.  Peter Kirkpatrick, Won't get fooled again, Nature Reviews Drug Discovery, 4(8): 630, August 2005  rotean ligands: The literature contains few examples of ligands that seem to be able to both promote and decrease activity at the same G-protein-coupled receptors. Such 'protean ligands' — so- called after the mythical character Proteus, who could adopt any shape he desired — have been proposed to work by acting as agonists with low efficacy. They thereby increase the activity of receptors that are basically silent under resting conditions, but decrease the activity of receptors that have high levels of ligand- independent, spontaneous (or constitutive) activity. In this model, protean behaviour therefore depends on having two populations of receptors with different levels of spontaneous activity. Adam Smith, Adrenoceptor pharmacology: How the ligand changed its spots Nature Reviews Drug Discovery 1, 569 Aug. 2002  http://www.nature.com/cgi-taf/Gateway.taf?g=5&file=/drugdisc/res_high/articles/nrd885.html&filetype=&_UserReference=

protease inhibitors:  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.  Developments reviewed in this report indicate that more protease inhibitors, several having significant commercial potential, will reach the market over the next three to four years. Insight Pharma Reports, Protease inhibitors: Innovation drives drug pipeline, 2009 

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

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 2.7.1.37.  MeSH, 1980  Broader term: kinases Narrower terms: -Omes & -omics kinome,  kinomics

protein kinase inhibitors: Agents that inhibit PROTEIN KINASES. MeSH 2005
Protein kinase evolution, SUGEN, 2002 http://www.kinase.com/evolution/

protein- protein interactions: Protein-protein interactions (PPI) play a key role in many biological processes, making them promising targets for drug discovery. Though inhibition of protein-protein interactions has been challenging due to binding-site characteristics at the protein-protein interface, there has been considerable success in recent years.  Protein Protein Interactions as Drug Targets: Drug Discovery Chemistry April 13-14, 2011 San Diego CA 

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  http://www.springer.com/biomed/pharmaceutical+science/book/978-3-540-72842-9

Can be detected by yeast two- hybrids, phage display or immunoprecipitation assays.  John A Wagner "The logic of molecular approaches to biological problems" Cornell University Medical College http://www-users.med.cornell.edu/~jawagne/logic_&_experimental_desig.html 

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.

protein targets: The purpose of the "PDB ligands" link is to give, at a glance, a quick way of determining if compounds in the selected SOM cluster have any "known" protein targets and if any homologous human proteins exist. The PDB ligands link from each cluster page provides connections to structural data as deposited in the Protein Data Bank (PBD). PDB Ligands Summary http://spheroid.ncifcrf.gov/spheroid/ManPages/ManPdbLigands.cfm  Google = about 2,340 Aug. 24, 2002; about 3,790 Aug. 27, 2003; about 7,710 June 10, 2004; 133,000 Nov 13, 2004; about 154,000 May 25, 2007, about 318,000 Jan 10 2011

proteomimetics-- small molecule:  The interaction between proteins is fundamental to many receptor- ligand, enzyme- substrate, and protein- protein interactions that have been linked to human disease states. Given the large number of novel protein targets emerging from the genome and the dearth of small molecules known to bind to and antagonize these targets, the challenge presented to the pharmaceutical industry is in the identification of novel agents effecting these novel targets. Traditional screening methods can be augmented by directed discovery efforts that seek to capture the essence of a protein's binding epitope in the context of a small molecule. Folding@home glossary, Stanford Univ. http://www.stanford.edu/group/pandegroup/folding/education/P.html  Related term: protein small molecule interactions  Google = about 43 July 14, 2004, about 327 Oct. 25, 2006

proteonomics: Expression systems that can rapidly produce high levels of recombinant proteins are a critical link between the discovery of new genes and the identification of targets and molecules for drug development. Advances in the baculovirus expression technology makes it the system of choice in the emerging field of proteonomics where rapid production and high yields of biologically active complex proteins are essential in the discovery of new drug targets, vaccines, and biotherapeutics. Folding@home glossary, Stanford Univ. http://www.stanford.edu/group/pandegroup/folding/education/P.html Google = about  593  Sept. 18, 2002; about 805 Aug 18, 2003; about 3,530 July 14, 2004; about 10,200 Nov. 5, 2005; about 17,300 Nov 10, 2006  Related term: proteomics  

prototypes: First in class compounds usually directed at a specific molecular target. (Note that we have adapted the term for use in a broader sense to replace the term lead compound, which arguably loses some of its meaning after the4 lead optimization process.)  Insight Pharma Reports, Backup Compound Strategies: Best Practices for Reducing Phase II Risk, 2007

receptor: A protein or a protein complex in or on a cell that specifically recognizes and binds to a compound acting as a molecular messenger (neurotransmitter, hormone, lymphokine, lectin, drug, etc.). In a broader sense, the term receptor is often used as a synonym for any specific (as opposed to non- specific such as binding to plasma proteins) drug binding site, also including nucleic  acids such as DNA. IUPAC Computational  Narrower terms: amino acid receptors, cell surface receptors, drug receptors, receptor mapping In silico & Molecular modeling; Related terms:  Cell biology ligand; 

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: Molecular Medicine gene therapy

RNAi screening: RNA interference (RNAi) is being commonly used as a screening tool for identifying and validating potential drug targets, exploring unknown cellular pathways, and for performing whole-genome functional screens. The screens developed, using both small interfering RNA (siRNA) and short hairpin RNA (shRNA), are now fairly robust and sensitive and can be performed in a reliable and high-throughput fashion.  Discovery on Target RNAi for Functional Screening November 3-4, 2011 • Boston, MA Program | Register | Download Brochure 
 

Related terms: Genomic Technologies: RNAi ; RNA shRNA, siRNA

selectivity: The word selectivity describes a drug's ability to affect a particular cell population in preference to others. As part of the current state of art in the search for new therapeutic agents, the property of selectivity is a mode of action thought to have a high degree of desirability....  Selectivity is generally a worthy property in a drug because a drug having high selectivity may have a dramatic effect when there is a single agent that can be targeted against the appropriate molecular-driver involved in the pathogenesis of a disease.  Promiscuous drugs compared to selective drugs (promiscuity can be a virtue) Simon K Mencher and Long G Wang, BMC Clinical Pharmacology 2005, 5:3 doi:10.1186/1472-6904-5-3 http://www.biomedcentral.com/1472-6904/5/3/abstract   Related term: promiscuous drugs

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 targets. Related 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  
Google = about 666, Aug. 24, 2002; about 1,780 June 10, 2004; about 26,100 Nov 13, 2006

target credentialing: Identification of target molecules, evidence of modification of the target molecule, and measurement of desired effect. Clinical Radioresistance of Primary Glial Tumors, Radiation Biology, Progress Review groups, NINDS http://www.ninds.nih.gov/find_people/groups/brain_tumor_prg/RadiationBiology.htm 

There are now agents in clinical trial or about to enter clinical trial that have been designed against a specific molecular target. The putative target for a number of these agents has also been associated with radioresistance. Such agents will be evaluated for their ability to modify tumor cell radiosensitivity. Critical to these studies will be the establishing a causal relationship between the agent-induced modification of the target and radiosensitization. This will serve to validate (or invalidate) a given molecule as a target for radiosensitization (target credentialing) and establish a "marker" for the use in the potential design of a clinical trial. Although initial studies will be performed using tumor cell lines and normal cells in vitro, agents found to be effective in vitro will then be evaluated using in vivo models.  Molecular Radiation Therapeutics Branch, National Cancer Institute http://www3.cancer.gov/rrp/mrtb.html 
Google = about 9, Aug. 24, 2002; about 24 June 10, 2004; about 49 Nov 13, 2006; about 71 Oct 8, 2007, about 198 Jan 11 2011

target evaluation: The shift from traditional to genomics-and proteomics-based drug discovery has fundamentally changed the way researchers view the subject of targets. After decades of focusing on a few hundred relatively well-characterized therapeutic targets, drug developers are now finding that the genomics revolution has presented them with the opposite dilemma: thousands of prospective targets about which little is known. Insight Pharma Reports, Powering Discovery through Target Evaluation: Moving beyond the validation paradigm, 2005 http://www.insightpharmareports.com/reports/2005/52_TargetValidation/overview.asp 

Can cover the range of target- winnowing strategies, from target identification to target validation.   Google = about  1,650, Aug. 24, 2002; about 1,780 Aug. 27, 2003 [not all relevant]; about 2,780 June 10, 2004; about 34,500 Nov 13, 2006; about 38,100 June 25, 2007

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 http://www.ncbi.nlm.nih.gov/pubmed/12927511 

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 gene families:  small molecule leads — identified by virtue of their interaction with a single member of a gene family — are used to study the biological role of other members of that family, the function of which is unknown. Chemogenomics: an emerging strategy for rapid target and drug discovery, Markus Bredel & Edgar Jacoby, Nature Reviews Genetics 5, 262-275 April 2004  http://www.nature.com/nrg/journal/v5/n4/box/nrg1317_BX1.html  See also Chemistry chemogenomics  Google = about 95 Nov 13, 2006; about 5,210 June 25, 2007, about 4,370 Oct 8, 2007

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 development. Related 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 www.messebasel.ch/miptec/ .%5Cpdf%5CGEN_July_Aldridge.pdf   Related term?:  Assays lead hopping  Chemistry scaffold hopping 
Google = about 27 Aug. 26, 2003; about 30, June 10, 2004; about 70 Apr. 27, 2005; about 485 Nov 13, 2006; about 284 Nov 16, 2007

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:  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.   Google = about  14,800, Aug. 24, 2002; about 22,900 Aug. 26, 2003; about 37,600 June 10, 2004; about 494,000 Nov 13, 2006

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  Google Aug. 26, 2003  "target labelling" = about 80; about 136 June 10, 2004; about 530 Nov 13, 2006   "target labeling" = about 418; Aug 26, 2003; about 943 June 10, 2004; about 19,800 Nov 13, 2006

target molecules: Target genes or target proteins.  Google = about  6,480, Aug. 24, 2002' about 11,300 Aug. 26, 2003; about 21,000 June 10, 2004; about 473,000 Nov 13, 2006 

target prioritization:  Target prioritization is today a bottleneck as a result of the new genomics based drug discovery. Given the exponential increase in targets provided by the new technologies as gene expression analysis, no company can afford to advance all of the targets identified. Our Markets: The Drug Discovery Industry, InNetics http://innetics.com/markets.htm 
Google = about  422, Aug. 24, 2002; about 476 Aug. 26, 2003; about 517 June 10, 2004; about 911 Nov 13, 2006; about 11,000 May 25, 2007

target product profiles: A tool for planning in the development phase of R&D projects. Insight Pharma Reports, Backup Compound Strategies: Best Practices for Reducing Phase II Risk, 2007 

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  http://www.ercim.org/publication/Ercim_News/enw43/zien.html 
Google = about  8,610, Aug. 24, 2002; about 20,000 Aug. 26, 2003; about 36,900 June 10, 2004; about 740,000 Nov 13, 2006, about 863,000 Oct 8, 2007

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

target screening: Identifying molecules that may be associated with a disease process (e.g., upregulation of a particular gene identified through gene expression analysis). CHA, Cambridge Healthtech Advisors Model Animal Systems: Emerging Applications and Commercial Opportunities in Drug Discovery and Development, report, 2004  Related terms: target glut, target identification, target validation  Google = about 799, Aug. 24, 2002; about 1,230 Aug. 26, 2003; about 2,050 June 10, 2004; about 73,600 Nov 13, 2006

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 http://www.jcsg.org/help/robohelp/Definitions/Target_Selection.htm   http://www.nigms.nih.gov/News/Reports/psi_targetselect.htm 

target space: Structure-Based Drug Design (SBDD) has been in use within the pharmaceutical industry for over twenty-five years. SBDD continues to play an important role in drug discovery, design and optimization. Moreover, with the development of sophisticated biophysical and computational methodologies SBDD is impacting hit identification and ‘hit to lead’ optimization approaches across the industry.  Therapeutic Target Space DVD 2010  

target validation:  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. CHA, Cambridge Healthtech Advisors Model Animal Systems: Emerging Applications and Commercial Opportunities in Drug Discovery and Development, report, 2004

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 clearly means different things to different people.  Google = about  6,580, Aug. 24, 2002; about 10,300  Aug. 26, 2003; about 17,600 June 10, 2004, about 281,000 April 24, 2006; about 282,000 Nov 13, 2006; about 244,000 May 25, 2007

target validation technologies: 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 capable of interfering with targeting molecules that are needed for carcinogenesis and tumor growth. The benefit of targeted therapy is that cancer cells are attacked without harming normal cells.  TARGET Therapeutically Applicable Research to Generate Effective Treatments , National Cancer Institute Glossary http://target.cancer.gov/resources/glossary/ 

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: http://xin.cz3.nus.edu.sg/group/cjttd/ttd.asp  Computational Science Dept, Science Faculty, 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 
Google = about 175 June 10, 2004; about 586 Nov 13, 2006

Bibliography
IUPAC Compendium of targets of the top 100 commercially important drugs current project 2004-025-1-700 http://www.iupac.org/projects/2004/2004-025-1-700.html  
IUPAC  International Union of Pure and Applied Chemistry, Glossary of Terms used in Bioinorganic Chemistry, Recommendations, 1997. 450+ definitions. http://www.chem.qmw.ac.uk/iupac/bioinorg/
IUPAC Glossary of Terms used in Biomolecular Screening, IUPAC Recommendations 2008  provisional recommendations about 150 terms defined
IUPAC International Union of Pure and Applied Chemistry, Glossary of Medicinal Chemistry, 1998. 100+ terms. http://www.chem.qmw.ac.uk/iupac/medchem
MeSH Medical Subject Headings, (PubMed Browser) National Library of Medicine, Revised annually.  250,000 entry terms, 19,000 main headings. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=MeSH&term= 

Drug targets Conferences http://www.healthtech.com/Conferences/Upcoming.aspx?s=TRGS 
Discovery on Target http://www.healthtech.com/DOT/
Drug targets CDs, DVDs http://www.healthtech.com/Conferences/CompactDiscs.aspx?s=TRGS 
Drug targets Short courses http://www.healthtech.com/Conferences_Upcoming_ShortCourses.aspx?s=TRGS 

Insight Pharma Reports Drug targets series http://www.insightpharmareports.com/Reports/All.aspx?s=TRGS 
Insight Pharma Reports Cytokine Therapeutics: A Vibrant Pipeline and Active Approved Market Full Report | Executive Summary  2007
Insight Pharma Reports GPCRs: Dawn of a New Era? Full Report | Executive Summary  2008
Insight Pharma Reports Ion Channel Modulator Pipelines  2009 
Insight Pharma Reports Kinase Therapeutics: Pipeline Assessment and Commercial Prospects  2010
Insight Pharma Reports Nuclear Receptors: The Pipeline Outlook  2010 
Insight Pharma Reports Protease Inhibitors: Innovation Drives Drug Pipeline Full Report | Executive Summary  2009

Alpha glossary index

How to look for other unfamiliar  terms

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