Evolving Terminology for Emerging Technologies
Comments? Suggestions? Revisions? mchitty@healthtech.com
Last revised December 21, 2001
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Related glossaries include Applications Business of the life sciences, Clinical trials, drug, device & diagnostics approvals Functional Genomics, Genomics,  Proteomics, Pharmacogenomics.  Informatics Algorithms & data management, Bioinformatics, Chemoinformatics, Molecular modeling, Technologies  Assays, Labels, Signaling & Detection, Gene amplification & PCR, Mass spectrometry,  NMR & X-ray Crystallography  Biology Biomolecules,  Pharmaceutical biology  Additional definitions appear in the In-depth glossary, after the Bibliography.

96, 384, 1536, 3456 well plates: See under microtiter/ microtitre plates.

antigenic mimicry: See under molecular mimicry

antisense oligonucleotides: Pharmaceutical biology glossary

assay: Assays, labels, signaling & detection glossary  Related term screening

automation: Automating processes is often a critical part of industrializing processes developed in the research lab.  Higher throughput, quality control and better reproducibility are part of this process.. Automation may be cheaper, particularly in the long run. See Related terms LIMS, robotics.

biochemical genomics: Functional genomics glossary

biologics: Drug approvals glossary

biomimetic synthesis: [Clayton Healthcock's] research has been concerned with developing strategies for streamlining the synthesis of complex, naturally occurring compounds. "A particularly powerful strategy," he said, "is 'biomimetic synthesis,' in which we guess how nature might assemble a particular molecule and then try to mimic this hypothetical route in the laboratory."  Heathcock's work in the total synthesis of natural products and the development of new synthetic methodology has been of major interest to the pharmaceutical industry as well as to the international academic community.  [Univ. of California- Berkeley news release "Organic chemist Clayton H. Heathcock named Dean of College of Chemistry at the University of California, Berkeley" 8/12/99]  http://www.berkeley.edu/news/media/releases/99legacy/8-12-1999.html

So-called because it is based upon insights into the biochemical processes which form the compounds in the living organisms.  [Bio- Organic Chemistry, Research School of  Chemistry, Australian National Univ. Annual Report 1999] http://rsc.anu.edu.au/RSC/ChemResearch/AnnualReport/Report99/BF-report.html

biopharmaceutical: Biopharmaceutical companies use biotechnology to develop innovative drugs. Data on this emerging sector is often incomplete. [Industry Canada, Canada's Business and Consumer Site "Pharmaceutical Industry Profile" 2001]  http://strategis.ic.gc.ca/SSG/ph01311e.html#bio

biotechnology: Business of the Life Sciences

blockbuster drugs: 90% of drugs marketed by big pharma bring in less than $180 million per year. Compare that number to the total cost of $350- 600 million for approving a single drug (including all the failures that lead up to it). Of course, one might think that the money can be made back in four years, but drugs have a huge maintenance cost in terms of regulatory compliance, marketing and sales. The margin on a drug- to- drug basis is very slim. This places the onus on the other 10% of drugs to be blockbusters – to more than make up for most of the other drugs that are earning far too little revenue. This is how the industry has structured itself around a blockbuster mentality – a reliance on drugs that bring in at least $500 million per year in revenue. Considering the odds of achieving blockbuster status, this is a very high-risk strategy. Pharmaceutical companies will have to change their ways if they are going to enter the new era of individualized medicine. [CHI Summit Pharmacogenomics]  Related terms  Business of the life sciences biotechnology, market fragmentation. pharmaceutical industry, 

bottlenecks - drug discovery: Breaking the Bottlenecks: Applying Genomics Throughout Drug Discovery and Development October 2001 Identifies the major bottlenecks in drug discovery and discusses how genomics- based approaches - including both existing and emerging technologies - can address these problems. http://www.chireports.com/content/reports/dealmaking.asp

building block: One of a number of  interchangeable reagents which can be used in combinatorial library synthesis, part of the structure of which becomes incorporated into the final product, i.e. its residue. See also diversity reagent, monomer. [IUPAC Combinatorial Chemistry]

Related terms: combinatorial chemistry, combinatorial synthesis, diversity In-depth: directed library, fully combinatorial, in situ scaffold formation, monomer, pool/ split, residue, sub- library, unbiased library

chemical genetics: Describes the use of small synthetic molecules, that elicit a phenotypic change by direct protein interaction, to identify key genes involved in a specific biological pathway of interest. In many cases existing drugs are used as the chemical probes whose overall effect is well established but whose mode of action is not well understood. Chemical genetic experiments therefore, present an opportunity to clarify the specific mode of action of well- known therapeutics. Chemical Genomics / Chemogenomics: High-Throughput Discovery of Disease Genes and Drugs, Nov. 16, 2001  • Boston, MA. 

As the term has traditionally been used, has referred to studies that uncover the genetically controlled pathways influenced by a single specific compound. Also used to describe a method pioneered by Stuart Schreiber (Harvard Medical School, Howard Hughes Medical Institute involving a phenotypic screen employing a vast library of small molecules that have been introduced into a cellular assay. ...  The coverage of such studies can be genomic, but the detailed activity information they provide is at the genetic level (one gene within a particular pathway) http://www-schreiber.chem.harvard.edu [CHI Structural Proteomics] Related terms chemical genomics, chemogenomics.

chemical genomics: The current wealth of gene sequence information available, in conjunction with recent advances in array based technologies, have facilitated a Chemical Genomic approach. High- throughput screening with small, highly specific synthetic molecules, against multiple protein targets, results in measurable phenotypic changes and presents an opportunity to do gene functional analysis and create new therapeutic leads at the same time.  Chemical Genomics / Chemogenomics: High- Throughput Discovery of Disease Genes and Drugs, Nov. 16, 2001  • Boston, MA.

A term at a crossroads.  Some groups (e.g., NeoGenesis) have used this term to describe the broader meaning of chemogenomics (i.e., target- oriented libraries screened against small molecules). Other experts believe this term is a better name for what Stuart Schreiber refers to as chemical genetics. [CHI Structural proteomics] Related terms chemical genetics, chemogenomics

chemical space: The heartland of this debate [about how many samples are enough] centres on the definition, and hence extent, of chemical space. More precisely, it focusses on the extent of chemical space that is accessible by chemical synthesis and which could be described as drug- like. [Martin J. Valler,  Darren Green  "Diversity screening versus focussed screening in drug discovery " Drug Discovery Today 5(7): July 2000] Related term: property space http://162.105.138.23/pdl/web_course/swjs/diversity%20screening%20versus%20focussed%20screening%20in%20drug%20discovery.pd

chemogenomics: (Sometimes referred to as chemical genomics) was most likely first used by Vertex Pharmaceuticals to describe its parallel drug design approach, which involves using structures of proteins in a given family to design drugs for the family as a whole.  The Vertex approach is truly parallel (i.e., involving multiple targets at once) and combines structural biology, biased library design and screening, and structure- based drug design. At its limit, chemogenomics represents the discovery and description of all possible compounds that can interact with any protein encoded by the human genome. The term chemogenomics is slowly (and somewhat grudgingly) catching on.  Broadly, it now appears to mean “taking a combinatorial approach to screening protein targets by family/ class.” Detailed protein structure information is used to design libraries that are “biased” to contain compounds that are more likely to interact with a particular protein family (hence, it is a “genomic” approach).  This screening methodology helps researchers identify the best small molecule compound to bind to a target (hence it is a “chemical” approach). [CHI Structural Proteomics]

Chemogenomics is an emerging new field in which small molecule leads, identified for one member of a gene family, are used to elucidate the function and biological role of another member of that family, whose function is not known as well as identify potential drug leads. Both Chemical Genomics and Chemogenomics represent newer approaches to target identification and drug development with the potential for dramatically accelerating the process.  Chemical Genomics / Chemogenomics: High-Throughput Discovery of Disease Genes and Drugs, Nov. 16, 2001  • Boston, MA

May be defined, at the limit, as "all possible drugs against all possible targets". We will discuss some of our ongoing efforts in this area, emphasizing the essentially parallel nature of the process. Mark Murcko "Chemogenomics at Vertex" Chemical Genomics / Chemogenomics: High-Throughput Discovery of Disease Genes and Drugs, Nov. 16, 2001  • Boston, MA

Related terms chemical genetics, chemical genomics

clinical trials: Clinical genomics glossary

combichem: See combinatorial chemistry

combinatorial biosynthesis: Combinatorial biosynthesis of focused libraries of natural products holds great promise for capitalising on hardwon natural product leads. Miniaturisation of screens is required to reduce the cost of screening combinatorial libraries. Developments in the processes preceding and following synthesis are required to enable the flow of increased numbers of compounds without new bottlenecks developing. The impact of combinatorial chemistry will be greatly enhanced by synergy with ongoing parallel developments in genetic technologies, screening technologies and bioinformatics. [D. Brown "Future pathways for combinatorial chemistry" Molecular Diversity 2 (4): 217- 222 April 1997]http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9249757&dopt=Abstract

combinatorial biology: Biomaterials glossary

combinatorial chemistry: Using a combinatorial process to prepare sets of  compounds from sets of  building blocks. [IUPAC Combinatorial Chemistry]  

In the early 1990's it was believed that combinatorial chemistry would revolutionize the drug discovery industry. Ten years later the route from design and synthesis of compound libraries to identification of lead structures is still long and costly. Synthesis of an almost unlimited number of organic compounds covering as much of chemistry space as possible is no longer the most cost effective and time saving approach to hit identification. Creating libraries, using biological target structure to inform chemical design, facilitated by quantum advances in structural genomics and computational capabilities, is a smarter, more efficient way to produce good initial leads. Considering solubility, permeability and other drug- like properties early in library design and introducing both target and lead structural constraints in lead development are further ways to ensure more compounds make it to trial.  Exploiting Molecular Diversity Feb. 11-12, 2002 San Diego CA

Note that there is not enough matter in the universe to prepare all possible combinatorial variations. Related terms combinatorial libraries, diversity, microtiter plates, molecular diversity;  In-depth: fully combinatorial, pool/ split.

combinatorial library: A set of compounds prepared by combinatorial chemistry. May consist of a collection of pools, or sub- libraries. Its composition may be described by the chemset notation. [IUPAC Combinatorial Chemistry] Broader term library Cell biology glossary Narrower terms In-depth biased libraries, combinatorial antibody libraries, directed libraries, focused libraries, pool, pool/ split libraries, sub- library, random libraries, unbiased libraries; Related terms combinatorial synthesis, scaffold In-depth fully combinatorial.

combinatorial synthesis: A process to prepare large sets of organic compounds by combining sets of building blocks. [IUPAC Medicinal Chemistry]

compound validation: A process to quickly determine whether a molecule identified in a screen or assay will eventually lead to a drug. If you look at the costs of developing compounds into drugs, the most costly failures result from toxicity or pharmacokinetic liabilities rather than from their failure to act on the target. [CHI Breaking Bottlenecks]

Dalton: Biomolecules glossary

data mining: Algorithms & data management glossary

de novo design: The design of bioactive compounds by incremental construction of a ligand model within a model of the receptor or enzyme active site, the structure of which is known from X-ray or NMR data. [IUPAC Medicinal Chemistry] Related terms Molecular modeling,  Pharmaceutical biology, NMR & X-ray crystallography

deconvolute: To render less complex; Process of optimizing an activity of interest by fractionating (normally by resynthesis, or by elaborating a partial library) a pool with some level of the desired activity to give a set of smaller pools. Repeating this strategy leads to single members with (ideally) a high level of activity and is termed iterative deconvolution.  [IUPAC COMBINATORIAL CHEMISTRY]

Narrower term: In-depth iterative deconvolution

dendrimer: Miniaturization glossary

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. [CHI Summit Pharmacogenomics] Broader term: target

diversity: The "unrelatedness" of a set of, for example, building blocks or members of a combinatorial library, as measured by their properties such as atom connectivity, physical properties, computational measurements, or  bioactivity. [IUPAC Combinatorial Chemistry]  Narrower term molecular diversity, Related terms diversity screening, In-depth binning, cluster.

diversity screening: The drivers behind the current ethos of large- scale diversity HTS are rooted in the desire to build an improved hit identification process, and are based on the simple model of testing everything. The key activity over the past five or so years has been scaling: taking the existing model and increasing capacity by application of technology. [Martin J. Valler,  Darren Green  "Diversity screening versus focussed screening in drug discovery " Drug Discovery Today 5(7): July 2000]  http://162.105.138.23/pdl/web_course/swjs/diversity%20screening%20versus%20focussed%20screening%20in%20drug%20discovery.pd

docking: Molecular modeling glossary

drug: Drug approvals glossary

drug design: Includes not only ligand design, but also pharmacokinetics (Pharmacogenomics) toxicity, which are mostly beyond the possibilities of structure- and/ or computer- aided design. Nevertheless, appropriate chemometric (Chemoinformatics) tools, including experimental design and multivariate statistics, can be of value in the planning and evaluation of pharmacokinetic and toxicological experiments and results. Drug design is most often used instead of the correct term  "ligand design”.  [IUPAC Computational]

The molecular designing of drugs for specific purposes (such as DNA- binding, enzyme inhibition, anti- cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer- assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [MeSH]

An iterative process involving drug discovery, lead optimization and chemical synthesis with the aim of maximizing functional activity and minimizing adverse effects. Narrower terms rational drug design, structure- based drug design, In-depth molecular design; Algorithms & data management 3D-QSAR, QSAR;  Molecular modeling Computer Aided Molecular Design, Computer Assisted Drug Design CADD, Computer Assisted Molecular Modeling CAMD, de novo design 

drug development: Process of optimizing compounds following drug  discovery. Related terms lead optimization, lead validation.

drug discovery: As the lexicon of major genomes near completion, high throughput technologies continue to have a role in the identification of single nucleotide  polymorphisms (SNPs), tracking the functional relationships among genes and proteins and the identification of genes responsible for complex diseases. Microarrays and other massively parallel technologies have placed the focus on identifying biological pathways and the interactions between the potential drug targets that make up those pathways. The impact of high throughput technology has even led to the emergence of a new R&D organizational structure - around the drug targets rather than around specific diseases. Drug Discovery Japan: Exploiting Genomic, Chemical and Computational Advances  Jan. 28-30 2002 Tokyo, Japan

drug discovery- genomics based: Has the potential to identify those target molecules (including genes and proteins that do not belong to the target families addressed by current drugs) that underlie disease processes themselves, as opposed to symptoms. Together with structural proteomics, advanced chemical technologies (e.g., combinatorial chemistry technologies that involve the creation of diverse small- molecule libraries, chemical genomics and chemogenomics), and high- throughput screening, genomics- based drug discovery thus has the potential to create drugs that can address large unmet medical needs. However, good methods of target identification and validation will be necessary to realize this potential. [CHI Target Validation]

drug discovery pipeline: The process of drug development has evolved into an extremely complex procedure. The average drug takes 12 years and $270 million from initial discovery to public usage.(1) For every drug that is deemed marketable by the FDA, thousands of others are considered either unsafe or ineffective clinically. Beginning with preclinical research, new chemical entities (NCEs) are discovered in laboratories and tested in animals for safety and biological activity. If a compound is thought to be safe and effective as a chemical agent, a pharmaceutical company then submits an investigational new drug application (NDA) to the FDA. Once approved for clinical studies, a three-phase process begins where safety and efficacy are continually assessed with increased scrutiny and an increasing patient population. Approximately 70% of drugs entering clinical trials complete Phase I, 33% complete Phase II, and 27% complete Phase III.1 After Phase III is completed a company then submits a NDA to the FDA. Those drugs that are approved for marketing comprise an extremely small percentage of new chemical entities (NCEs) that are tested. In fact, from thousands only a handful of drugs undergo clinical studies, and even fewer receive market approval. [C. Daniel Mullins et. al. " Projections of drug approvals, patent expirations and generic entry from 2000 to 2004" report prepared for the Dept. of Health and Human Services' Conference on Pharmaceutical Pricing Practices, Utilization and Costs August 8-9, 2000, Washington DC, US] http://aspe.hhs.gov/health/reports/Drug-papers/Mullins-Palumbo%20paper-final.htm

Traditionally the movement of compounds along the pipeline has been a fairly linear process.  Because ways of speeding up the process can be enormously economically rewarding, greater attention is being paid to moving compounds along faster, trying to insure that compounds which will eventually fail, fail earlier, and looking at ways of revising the process to perform some evaluations in parallel rather than sequentially. 

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 term: protein target

druggable: Able to be modulated by a small molecule to produce a desired phenotypic change in cell targets. [CHI Functional Genomics]  

Variant spelling is drugable, however Google has about 283 hits for druggable, with about 138 for drugable (Nov. 16, 2001).

Related terms low hanging fruit, pharmaceutically tractable, small molecules, tractable targets In-depth privileged structure; Pharmaceutical biology G proteins, ion channels

efficacy: Pharmaceutical biology glossary

fail fast approach: Designed to eliminate high risk compounds at an early stage, is designed not to increase the throughput capacity of clinical development, but to free up existing capacity for more successful compounds. The industry will be faced with an increasing number of candidates and targets advanced into development as a result of many factors, including the availability of the human genome sequence. But companies risk actually decreasing their productivity rate if they end up chasing more low quality drug candidates. [CHI Summit Report Transforming the Pharmaceutical Industry  2001]

fluidic system: Device for synthesis or screening in which fluids such as reagents or assay buffers may be directed to specified locations by the opening and closing of valves in a stationary network of tubes and wells. Related term, robotic systems; Narrower term microfluidics Miniaturization glossary

focussed screening: Focussed screening is now well established as a successful hit generation strategy. With focussed screening, it should also be possible to use an assay that is more appropriate, rather than one that works well at a large scale. [Martin J. Valler,  Darren Green  "Diversity screening versus focussed screening in drug discovery " Drug Discovery Today 5(7): July 2000]  http://162.105.138.23/pdl/web_course/swjs/diversity%20screening%20versus%20focussed%20screening%20in%20drug%20discovery.pd

frontal affinity chromatography: Chromatography & electrophoresis glossary

high throughput organic synthesis: Combinatorial chemistry has resulted in the rapid expansion of compound libraries to keep pace with the demands of HTS screening. The ability to do novel chemistry on solid support has allowed for a vast array of compounds to be synthesized and subsequently screened for hits. Recent developments in multistep solution- phase synthesis have provided even more expansive ways to create diverse chemical libraries with a general trend toward quality and purity in conjunction with productivity's becoming more prevalent. This conference will highlight recent novel chemistries and reaction strategies, as well as optimization of reactions for library synthesis. Case examples of resins, linkers, and cleavage methods that make compound synthesis easier, faster, and more practical will be presented with emphasis on quality and high- throughput purification techniques.  High-Throughput Organic Synthesis Feb. 14-15, 2002 San Diego CA

High Throughput Screening HTS: Process for rapid assessment of the activity of samples from a combinatorial library or other compound collection, often by running parallel assays in plates of 96 or more wells. [IUPAC Combinatorial Chemistry] 

For any given target, HTS remains the predominant tool for identifying leads for further drug development. Those companies that can effectively deal with the flood of large numbers of potential targets coming out of genomics are those that can gain a significant competitive advantage. However, this abundance of new targets is both an opportunity and a threat. When companies are able to prioritize and validate targets, it allows them to narrow the focus to those leads offering improved chances of success. Those unable to keep up in this new "parallel" world will be left behind in the quagmire of huge expenditures in time and money. The inability to effectively validate and prioritize this large number of potential targets - many more than just a few years ago- means the risk of failure is even higher than failure rates of the past. This conference will explore the new techniques and technologies for speeding the drug discovery process and providing the best possible leads to continue through the pipeline. High- Throughput Screening: Intelligent drug discovery and development May 6-8, 2002 Philadelphia, Pennsylvania 

Broader term screening Related term throughput, Narrower term ultra high throughput screening.

hit:  Library component whose activity exceeds a predefined, statistically relevant threshold. [IUPAC Combinatorial Chemistry] Related terms HTS, lead discovery, screening. Narrower term progressible hit

A molecule with robust dose­ response activity in a primary screen and known, confirmed structure. The output of most screening. [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]  http://162.105.138.23/pdl/web_course/swjs/diversity%20screening%20versus%20focussed%20screening%20in%20drug%20discovery.pdf

intelligent drug discovery: Intelligent drug discovery and development May 6-8, 2002 Philadelphia, Pennsylvania 

LIMS Laboratory Information Management Systems: Most LIMS products allow the laboratory to; register work requests; print analytical worksheets; monitor and communicate sample/ technique backlogs; schedule work; acquire and store analytical data; monitor the quality of all analytical work; approve analytical data for client release; print and store analytical reports and invoices; protect the security of all data; track and locate samples in storage; track and communicate all quality control in the laboratory; provide laboratory management with production and financial statistics and with client information, e.g., names, addresses, sales figures, etc. An appropriately designed and installed LIMS can quickly bring accuracy and accessibility to the flow of samples and data in any laboratory. The real value of a LIMS is the ability to maximize sample throughput and minimize labor costs. [Dan Bentley, "Analysis of a Laboratory Information Management System (LIMS)" Nov., 1999 Univ. of Missouri St. Louis] Related terms robotic systems, robotics, sample prep. http://www.umsl.edu/~sauter/analysis/LIMS_example.html

lead: A representative of a compound series with sufficient potential (as measured by potency, selectivity, pharmacokinetics, physicochemical properties, absence of toxicity and novelty) to progress to a full drug development programme.  [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]  http://162.105.138.23/pdl/web_course/swjs/diversity%20screening%20versus%20focussed%20screening%20in%20drug%20discovery.pdf

Related term: hit

lead discovery: The process of identifying active new chemical entities, which by subsequent modification may be transformed into a clinically useful drug. [IUPAC Medicinal Chemistry] Related terms drug discovery, hit, lead generation, lead optimization, screen

lead generation: Strategies developed to identify compounds which possess a desired but non- optimized biological activity. [IUPAC Medicinal Chemistry] Related terms drug development, hit, lead discovery, lead optimization.

lead optimization: The synthetic modification of a biologically active compound, to fulfill all stereoelectronic, physicochemical, pharmacokinetic and toxicologic required for clinical usefulness. [IUPAC Medicinal Chemistry] Related terms drug development; ADME. Pharmacogenomics glossary

The large number of leads emerging from genomics and combinatorial chemistry demands that a new paradigm of lead optimization must be found. This new paradigm demands that companies move to parallel processes that evaluate binding affinity, ADME, drug properties, etc. earlier in the process in order to cut the time and costs lost in failed leads. It also brings new challenges and complications to the field. With the emergence of new technologies to help better identify the most promising leads a critical issue remains the validation and acceptance of these methods by regulatory agencies, as well as having the ability to run in parallel with other techniques in order to accelerate lead selection decisions. This meeting covers the crucial issues, implications, and strategies that allow you to employ new ways of reaching these goals faster, better and more economically. In addition, delegates will learn new techniques to improve existing leads to make them viable choices to continue through the drug development pipeline. Smarter Lead optimization: Intelligent drug discovery and development May 6-8, 2002 Philadelphia, Pennsylvania 

lead selection: See lead discovery

lead validation: With no shortage of drug targets, increasing emphasis is being placed on lead validation. One key challenge is developing high throughput screens. Related term target validation.

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] Related term drug design, molecular design;  Pharmaceutical biology glossary ligand

 ligand-directed drug discovery: The first goal is to select a small number of likely targets (which at least in some cases, such as targets in pathogens, are validated targets) rapidly, without the need for costly and time-consuming biologically based target validation and functional determination. The second goal is to obtain lead compounds for these targets, instead of starting with a biologically validated target and then attempting to screen libraries for lead compounds that modulate it. [CHI Breaking Bottlenecks]

low hanging fruit: The easiest drugs to identify and gain approval for.  The big question these days is how much (if any) "low hanging fruit" is left. Related terms druggable, pharmaceutically tractable, tractable targets

medicinal chemistry: A chemistry based discipline, also involving aspects of biological, medical and pharmaceutical sciences. It is concerned with the invention, discovery, design, identification and preparation of biologically active compounds, the study of their metabolism, the interpretation of their mode of action at the molecular level and the construction of structure- activity relationships [IUPAC Medicinal Chemistry]

microplate: See microtiter plate, microtitre plate.

microtiter plate, microtitre plate: Sample holding device used in combinatorial chemistry and high throughput screening for cloning of PCR products and construction of cDNA libraries in expression vectors. Comes in 96, 384, 1536 and 3456- well formats. Related term sample

The microplate reader was created from the tube spectrophotometer designs of the 1970s to save precious antibody samples. At first clumsy and inaccurate, absorbance microplate readers have evolved to pack unbelievable power and precision, replacing cuvette spectrophotometers for most multisample applications.¹ Continuous improvement is enhancing the classic designs to embrace the world of high- throughput (HT) screening and to allow complete analytical automation.² To handle the HT range (more than 10 microplates a day or 1,000 assays), many instruments now allow robotic handling of plates "stacked" in accessory plate handlers.  [Jorge D. Cortese " Well Read: Technological improvements are pushing microplate readers into the 21st century's high-speed, computerized world" Scientist 14 (19): 24, Oct. 2, 2000]  http://www.the-scientist.com/yr2000/oct/profile_001002.html http://www.the-scientist.com/yr2000/oct/profile_001002.html

Profile of specialty microwell plates, Scientist 13 (19): 16 Sept. 27, 1999 http://www.the-scientist.com/yr1999/sept/profile1_990927.html  

UV/VIS microplate readers, Scientist 12 (14): 18 July 6, 1998 http://www.the-scientist.com/yr1998/july/profile1_980706.html

monomer: Member of a building block set which can be repeatedly incorporated into a library to give a set of compounds of repeating structure; e.g. amino acids in a peptide library. [IUPAC COMBINATORIAL CHEMISTRY]

molecular design: The application of all techniques leading to the discovery of new chemical entities with specific properties required for the intended application. [IUPAC Compendium] Related terms drug design, ligand design, rational drug design.

molecular diversity: Covers combinatorial chemistry, combinatorial libraries, solid- phase synthesis, robotics, molecular graphics: The visualization and manipulation of three- dimensional representations of molecules on a graphical display device. [IUPAC Medicinal Chemistry] 

In the early 1990s it was believed that combinatorial chemistry would revolutionize the drug discovery industry. Ten years later the route from design and synthesis of compound libraries to identification of lead structures is still long and costly. Synthesis of an almost unlimited number of organic compounds covering as much of chemistry space as possible is no longer the most cost- effective and time- saving approach to hit identification. Creating libraries by using biological target structure to inform chemical design, facilitated by quantum advances in structural genomics and computational capabilities, is a smarter, more efficient way to produce good initial leads. Considering solubility, permeability, and other druglike properties early in library design and introducing both target and lead structural constraints in lead development are further ways to ensure that more compounds make it to trial. Anyone interested in learning how to develop more effective libraries faster and cheaper, as well as learning from case studies where informed design in conjunction with novel assay development has been successful, should attend this meeting. Exploiting Molecular Diversity   Feb. 11-12, 2002 San Diego CA 

Related terms combinatorial chemistry, drug design, high throughput organic synthesis; Molecular modeling glossary  Broader term diversity.

molecular mimicry: The process in which structural properties of an introduced molecule imitate or simulate molecules of the host. Direct mimicry of a molecule enables a viral protein to bind directly to a normal substrate as a substitute for the homologous normal ligand. Immunologic molecular mimicry generally refers to what can be described as antigenic mimicry and is defined by the properties of antibodies raised against various facets of epitopes on the viral protein. [MeSH from Immunology Letters 28 (2): 91-9 May 1991]

molecular recognition: The ability of biological macromolecules such as proteins and DNA to recognize selectively and to bind to other species to form larger supramolecular complexes is a key element in the extraordinarily diverse and controlled chemistry exhibited by nature. Chemists today are increasingly interested in mimicking these processes which involve 'molecular recognition' of one molecule by another via formation of specific nonequivalent bonds between them and spontaneous binding together of two to many thousands of molecules into well defined supramolecular systems with new chemical properties. Industrially important applications already include drug design, synthesis of stereo regular polymers, affinity chromatography, crystallization, epitaxial growth and liquid crystal displays. [BD More and M.J. Dustin Molecular Recognition course, University of Strathclyde, Glasgow, Scotland, 2000] Related terms molecular mimicry, peptidomimetic, recognition site. http://www.strath.ac.uk/Departments/Chemistry/courseinfo/4thyear/13944.html

multi component reactions MCRs: Represent an unique chemical concept towards the most efficient synthesis of a broad variety of chemical entities. Instead of building up desired molecules with sequences of known and established reactions one may design new MCRs yielding these molecules in one step by combining more than just two suitable starting materials. [MCR 2000 Munich, Germany]  http://www.mcr2000.org/1/index.html

multiwell plate: See microtiter plate, microtitre plate.

NCE New Chemical Entity: Drug approvals glossary

NME New Molecular Entity: Drug approvals glossary

organic synthesis: Narrower terms high throughput organic synthesis Related terms In-depth cleavage, linkers, resins, solid phase, solution phase, tether

orphan products: Drug approvals glossary

peptidomimetic: A compound containing ono- peptidic structural elements that is capable of mimicking or antagonizing the biological action (s) of a natural parent peptide. A peptidomimetic does no longer have classical peptide characteristics such as enzymatic ally scissile peptic bonds. [IUPAC Medicinal Chemistry]

Compounds that can mimic the critical features of the molecular recognition process of the parent peptide and thereby block or reproduce the action of the peptide. Peptidomimetics can in this definition thus be either antagonists or agonists. Probably the oldest example of a non- peptide peptidomimetic agonist for a peptide receptor system is morphine, that mimics the opioid peptides [Structure and Conformational Behaviour of Peptoid Peptidomimetics (thesis) Univ. Utrecht, Netherlands, 1997] http://www.pharm.uu.nl/thesis/boks/chapter_1/Chapter_1.html

Related terms: Omes & omics glossary peptidome, peptidomics

phage display: Functional genomics glossary

pharmaceutical industry: Business of the Life Sciences

pharmaceutically tractable: Related term druggable, low hanging fruit, tractable targets

pharmacophore: Pharmaceutical biology glossary

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] 

pharmainformatics: The multidisciplinary informatics needs of the pharmaceutical industry (HTS High Throughput Screening) data, combinatorial chemistry, ADME informatics, cheminformatics, toxicology, etc. information access and communication between various departments like the development and discovery teams. [CCL [Computational Chemistry List] call for papers, Spring ACS [American Chemical Society] meeting in San Diego (April 1-5, 2001) Sponsored by the Biotechnology Secretariat (BTEC) Co-sponsored by Chemical Information Division (CINF)]   http://www.quimica.urv.es/~bo/llistes/CCL/100/10/msg00081.html

pharming: Use of  transgenic animals to produce drugs in their milk, urine or eggs.  Transgenic plants can also be used. (Tobacco is said to be particularly amenable to this application).  

Related term: Genomics glossary crop genomics

phenotypic screen: See under chemical genetics

progressible hit: A representative of a compound series with activity via an acceptable mechanism of action and some limited structure­ activity relationship. [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]  http://162.105.138.23/pdl/web_course/swjs/diversity%20screening%20versus%20focussed%20screening%20in%20drug%20discovery.pdf

property space: Multidimensional representation of a set of compounds in which the axes represent quantifiable properties such as molecular weight, CLogP, molar refractivity, etc., and individual compounds are represented by a vector or set of coordinates. [IUPAC COMBINATORIAL CHEMISTRY] Related term chemistry space

protein target: Related terms structure- based design; NMR glossary  site-directed NMR analysis; Microarrays glossary small molecule microarrays 

Quantitative Structure-Activity Relationships (QSAR): Algorithms & data management glossary.

random screening: A staple of the pharmaceutical industry for many years. Now largely replaced by varying combination of combinatorial chemistry and/or rational drug design.  Related terms diversity screening, focussed screening Broader terms screen, screening

rational drug design: The goal of rational drug design is to use what is known about a disease or an infectious agent to create safer, more effective drugs that act specifically to prevent the disease. The scientific area of rational drug design and medicinal chemistry is a multidisciplinary field that requires contributions from experts in infectious diseases, biochemistry, chemistry, structural studies, chemical synthesis, pharmaceutical sciences, radiology and computer algorithms. [Research and External Affairs, University of Alberta, Canada]  http://www.ualberta.ca/~univhall/vp/vprea/MST99/eere/rat.htm  Related terms structure based design; see also Molecular modeling.  

recognition site: Pharmaceutical biology glossary

regulatory agencies: See Drug approvals glossary

reverse pharmacology: [Masashi] Yanagisawa [Howard Hughes Medical Institute at the University of Texas Southwestern Medical Center at Dallas] went after these receptors because they are mostly "orphan receptors"— those with no known ligand. He suspected that the ligand for many of these receptors would turn out to be a peptide hormone. The computer research yielded about 50 sequences that the group felt were likely to be G protein-coupled receptors, and then set about using those receptors as bait to capture peptide hormones, their true quarry. This strategy is known in the field as "reverse pharmacology.   "In traditional pharmacological research, the hormone is identified first," Yanagisawa said. "That hormone is then used as a tag to pull out the receptor molecule. We're doing this in reverse."  ['Hormones found that influence appetite' HHMI News Feb. 20, 1998]http://www.hhmi.org/news/orexin.html

robotic system: Automated device where materials are transferred by the physical movement of a delivery device relative to the ultimate receptacle, or vice versa. See also fluidic system. [IUPAC Combinatorial Chemistry]

robust: Algorithms & data management glossary

sample: 1. In statistics, a group of individuals often taken at random from a population for research purposes 2. One or more items taken from a population or a process and intended to provide information on the population or process. 3. Portion of material selected from a larger quantity in some manner chosen so that the portion is representative of the whole. [IUPAC Tox] Related Terms In-depth: aliquot, autosampler, biased sample, random sample, solid phase extraction, split sample. stratified sample, systematic sample. 

sample prep: For genomic studies, the quality of isolated nucleic acid sample is critical in obtaining data that is accurate and informative. With clinical material it is often imperative to obtain a homogenous sample or isolate individual cells. The stability and standard of final nucleic acid sample isolated are as much consequences of storage and handling of starting material as they are capture, extraction, or purification procedures. In addition, the volume of information being made available through sequencing efforts and advances in microarray and other technologies has amplified the need for rapid, high- standard, sample manipulation in conjunction with further miniaturization and automation of such processes. Genomic Sample Preparation  May 2-3, 2002 •  Boston, MA   

Related terms: Assays, labels, signaling & development glossary: single cell detection, single molecule detection

Related terms LIMS Laboratory Information Management Systems, In-depth aliquot, microtiter plate, solid phase extraction, split sample; Proteins glossary  depletion, pre- fractionation; Cell biology glossary LCM Laser Capture Microdissection, subcellular fractionation; others?

scaffold: Core portion of a molecule common to all members of a combinatorial library. [IUPAC Combinatorial Chemistry]  This is different from the scaffold defined in the Sequencing glossary. Narrower terms In-depth in situ scaffold, preformed scaffold.

scalable: Capable of being expanded for high- throughput. Analogous to recipes optimized for large groups, rather than standard recipes being quadrupled or more, with less than ideal results.

screen: An optimized, streamlined assay format with characterized robustness to diverse chemical types and conditions such that testing of 10,000 samples is both feasible and cost effective. The spectrum of low- throughput screening (10,000­ 50,000 assay points) medium- throughput screening (50,000­100,000 data points) and high- throughput screening (100,000­ 500,000 data points) can be defined. The scale of implementation of a given screen is greatly influenced by format, application of technology (e.g. automation), time and resource constraints. [The precise definition of the[se] 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] Related term screening http://162.105.138.23/pdl/web_course/swjs/diversity%20screening%20versus%20focussed%20screening%20in%20drug%20discovery.pdf

screening: Pharmacological or toxicological screening consists of a specified set of procedures to which a series of  compounds is subjected to characterize pharmacological and toxicological properties and to establish dose- effect and dose- response relationships. [IUPAC Tox]

The use of in vitro biochemical assays, or tests, to detect compounds which modulate the activity of a target (i.e., enzyme inhibitors, receptor agonists or antagonists). [Oxford Molecular]  

While drug screening is often talked about in the context of achieving hits, it is useful to note that the Oxford English Dictionary definition of screening specifies that this is "esp. for the detection of unwanted attributes or objects".  

Narrower terms diversity screening, focussed screening, HTS High Throughput Screening, synthetic lethal screening, Ultra High Throughput Screening UHTS; In- depth I.R> Thermography.   Not the same as screening in Clinical genomics glossary Related terms assay, target screening

small molecules: Preferred for drugs as they are orally available (unlike proteins which must be administered by injection or topically). Size of small molecules is generally under 1000 Daltons, but many estimates seem to range between 300 to 700 Daltons. Related term druggable. 

Related terms druggable, low hanging fruit, pharmaceutically tractable

solid support:  Insoluble, functionalized, polymeric material to which library members or reagents may be attached (often via a linker) allowing them to be readily separated (by filtration, centrifugation, etc.) from excess reagents, soluble reaction by- products, or solvents. [IUPAC Combinatorial chemistry]

Related terms: bead, high throughput organic synthesis, In-depth cleavage, gel phase, linker, pool/ split, resin, sort and combine

space: Narrower terms: chemical space, property space; In-depth spatially addressable

spatially addressable: Having the ability to identify at least part of the structure of a library component or pool by noting its physical location in an array. [IUPAC COMBINATORIAL CHEMISTRY]

Structure Activity Relationship (SAR): The relationship between chemical structure and pharmacological activity for a series of compounds  [IUPAC Medicinal Chemistry]

Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Other factors contributing to structure- activity relationship include chemical reactivity, electronic effects, resonance, and inductive effects. [MeSH]

Narrower terms Algorithms & data management  3D-QSAR, QSAR; Related terms NMR SAR by NMR ; Algorithms & data management cluster analysis, Principal Components Analysis PCA, recursive partitioning 

structure based design: A design strategy for new chemical entities based on the three- dimensional (3D) structure of the target obtained by X-ray or nuclear magnetic resonance (NMR) studies, or from protein homology models. [IUPAC Computational]

Based on a firm understanding of molecular recognition, between active site groups and interacting molecules and is a strategy that has become an integral part of modern drug discovery. For the past ten years, combinatorial chemistry and diversity- based high- throughput screening was the approach of choice for lead identification while computational methods were employed predominantly in lead optimization activities. Due to the recent volume and pace at which the 3-D structures of protein targets and their co- crystals have been made available, coupled with advances in computation tools, Structure-Based Drug Design has become a tool for lead generation as well as for optimization. Computational approaches to lead identification and design show many advantages over diversity- based, high- throughput screening, including reduced reagent storage and handling of large libraries, lowering of false positives often associated with HTS, and the ability to find low molecular weight leads even when HTS fails.  However, there is little doubt that the greatest advances in drug discovery will be achieved by combining the strengths of  computational and combinatorial chemistry/ HTS strategies. This conference will cover the latest advances in Structure-Based Drug Design methodologies including flexible, faster docking techniques, virtual screening and library design, target/ structure focused combinatorial chemistry and will highlight specific gene to lead, pre- clinical and clinical case examples..  Structure- based Drug Design: April 24- 25, 2002 Cambridge MA  

Since the early 1980s, industry has been interested in structural biology as part of the discipline of direct structure- based drug design, which combines structural biology with computational and medicinal chemistry in order to design drugs - rather than merely selecting drugs - that modulate a protein target of interest.  [CHI Structural proteomics] Broader term drug design. Related terms Molecular modeling glossary

substrate: Pharmaceutical biology glossary

synthesis: Narrower terms: biomimetic synthesis, high throughput organic synthesis, multi- component reactions, organic synthesis, solid phase synthesis, solution phase synthesis In-depth array synthesis, parallel synthesis

synthetic lethal screening: Functional genomics glossary

target: 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. [CHI Functional Genomics] Narrower terms disease targets, drug targeting,  target validation, tractable targets. See also target (hybridization) Gene amplification & PCR Glossary

Jurgen Drews, now chairman of International Biomedicine Management Partners, Inc. and formerly of Hoffman La Roche, notes that all drug therapy is based on the existence of 500 molecular targets.  He expects genomics to add thousands of new targets.

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. [CHI Consulting Services] http://www.discoverydeals.com/aboutconsulting.cfm  Related term target identification, target qualification, target validation

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. [CHI Target Validation] Related terms information overload, target identification, target screening, target validation

target identification: The process of identifying molecules that clearly play a role in a disease process. Target identification methods  provide a finer degree of detail than target screening. [CHI Target validation] 

Requires evidence that the gene/ protein is correlated with the disease.  [CHI Consulting Services] http://www.discoverydeals.com/aboutconsulting.cfm

Related terms target characterization, target glut, target qualification, target screening, target validation.

target qualification: The process of identifying molecules that clearly play a role in a disease process (e.g., upregulation of a particular gene identified through gene expression analysis). [CHI Breaking Bottlenecks]

target screening: Identifying molecules that may be associated with a disease process (e.g., upregulation of a particular gene identified through gene expression analysis). Screening approaches, such as data mining or genetic methods (e.g., positional cloning and single nucleotide polymorphism [SNP]- association studies) are used to identify new targets.  [CHI Target Validation] 

Broader term target, Related terms target glut, target identification, target validation.

target validation:  Determining that a molecular target is critically involved in a disease process and a potentially valuable point of intervention for new drugs. Probably the most important challenge facing the genomics- based drug discovery and development industry today [CHI Target Validation]

Requires evidence that modulation of the target results in the amelioration or reversal of a disease phenotype.  [CHI Consulting Services] http://www.discoverydeals.com/aboutconsulting.cfm

Involves taking steps to prove that a DNA, RNA or protein molecule is critical in a disease process and is therefore a suitable target for development of a new therapeutic compound. Sequence homology studies have successfully classified genes into target families such as GPCRs, ion channels and kinases. The enormous task of deciphering which of these targets, that share sequence but not function, are key players in disease and which should be used for subsequent drug development, needs to be addressed in a cost effective and efficient manner. Genes that do not belong to an established family are critical to many disease processes and also need to be validated as potential drug targets. This extends further the need for high- throughput approaches to determining which targets are a part of disease relevant pathways and should be exploited. Not only is it important to validate targets quickly and efficiently at the early stages of development, but to make the right choices to save time, resources and money in the later stages.  High- Throughput Target Validation  Nov. 14-15, 2001, Boston, MA

It is becoming clear that microarray analysis will be one of the first steps in target validation. [CHI Microarrays] 

The definition of target validation is clearly evolving, can be seen as "slippery" and means different things to different people. Related terms target characterization, target glut, target identification, target screening

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.

template: Sequences, DNA & beyond glossary In-depth

throughput: Output or production, rate at which something can be processed.  Narrower terms HTS High Throughput Screening, Ultra High Throughput Screening UHTS.

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 http://162.105.138.23/pdl/web_course/swjs/diversity%20screening%20versus%20focussed%20screening%20in%20drug%20discovery.pdf

Ultra High Throughput Screening (UHTS) : A screening rate of  100,000 assays per day. [IUPAC Combinatorial Chemistry] Broader term HTS High Throughput Screening.

xenobiotic: A compound foreign to an organism. From the Greek xenox = foreign, bios = life. [IUPAC Medicinal Chemistry] Principal xenobiotics include drugs, carcinogens and various compounds that have been introduced into the environment by artificial means. [IUPAC Bioinorganic]

Bibliography

[CHI Breaking Bottlenecks] Breaking the Bottlenecks: Applying Genomics Throughout Drug Discovery and Development,  CHI Reports, Nov. 2001.

[CHI Target Validation] Target Identification and Validation, Allan Haberman, Deidre Lockwood and Malorye Branca, Cambridge Healthtech Institute Report 10, June 2001.

Alpha glossary index

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

In-depth Drug discovery & development glossary

aliquot: (analytical chemistry) A known amount of a homogeneous material, assumed to be taken with negligible sampling error The term is usually applied to fluids. The term "aliquot" is usually used when the fractional part is an exact divisor of the whole; the term "aliquant' has been used when the fractional part is not an exact divisor of the whole. When a laboratory sample or test sample is 'aliquoted' or otherwise subdivided, the portions have been called split samples. [IUPAC Compendium] Related term sample prep.

array synthesis: Form of parallel synthesis in which the reaction vessels are  maintained in a specified spatial distribution, e.g. the wells of a 96-well plate or pins held in a rack [IUPAC COMBINATORIAL CHEMISTRY] Related term spatially addressable.

autosampler: Automated sample loader, usually robotic, used  with chromatography and other analytical technologies.

bead: (Normally spherical) particle of solid support. [IUPAC Combinatorial Chemistry] Related term microspheres; bead arrays Microarrays glossary

biased libraries: Libraries of compounds (putative drug leads) that exclude compounds unlikely to interact with particular protein family structures; these libraries are, therefore, “informed” by structure data. [CHI Structural genomics] Broader term combinatorial libraries.

binning: Approach to classifying the diversity of a set of compounds by grouping related members in "bins" on the basis of common physical or structural features. Commonly applied to the analysis of a set for the completeness of coverage of the desired property space. [IUPAC COMBINATORIAL CHEMISTRY]

cleavage: Process of releasing compound from solid support, thereby permitting assay or analysis of the compound by solution- phase methods. Dissolution of the compound following , rather than the cleavage step itself, may be rate- limiting. [IUPAC COMBINATORIAL CHEMISTRY]

Related term: solid support

cluster: Group of compounds which are related by structural or behavioral properties. Organizing a set of compounds into clusters is often used in assessing the diversity of those compounds, or in developing SAR models. See also binning; and principal components analysis, recursive partitioning (Algorithms). [IUPAC COMBINATORIAL CHEMISTRY].

combinatorial antibody libraries: Recent advances in the generation and selection of antibodies from combinatorial libraries allow for the rapid production of antibodies from immune and non- immune sources. This intensive laboratory/lecture course will focus on the construction of combinatorial antibody libraries expressed on the surface of phage and selection of desired antibodies from the library. Students will learn the theoretical and practical aspects of constructing combinatorial libraries from immune and non- immune sources as well as the construction of synthetic antibody libraries. Antibodies will be selected from the library by panning. [Cold Spring Harbor Laboratory, Phage Display of Combinatorial Antibody Libraries Nov. 6-19, 2001] Related term combinatorial libraries http://nucleus.cshl.org/meetings/2001c-mac.htm

directed library: (also biased- or focused library). Library which uses a limited number of  building blocks chosen on the basis of pre- existing information or hypothesis which defines the type of functionalities deemed important to obtain a particular activity. For example, every member of the diketopiperazine library shown below contains the thiol pharmacophore known to interact with metalloproteinase enzymes. Related term unbiased library. [IUPAC COMBINATORIAL CHEMISTRY]

focused library: See directed library.

fully combinatorial: Containing, or designed to contain, all possible combinations of building blocks. Pool/ Split libraries are generally fully combinatorial while parallel synthesis libraries may not be. See also reagent efficiency. [IUPAC COMBINATORIAL CHEMISTRY]

gel phase: Description applied to certain 'solid' supports which display properties intermediate between solid and liquid phases, e.g. in the apparent mobility of the support as determined by NMR spectroscopy. [IUPAC COMBINATORIAL CHEMISTRY]

I.R. Thermography Infrared thermography: Screening technique where the heat of reaction of a multitude of samples is simultaneously measured. Has been applied in particular to the screening of libraries of potential catalysts. [IUPAC Combinatorial Chemistry]

in situ scaffold formation: Process whereby a scaffold is formed during library production which contains residues of at least two building blocks; compare preformed scaffold. [IUPAC COMBINATORIAL CHEMISTRY]

iterative deconvolution: Multi- step application of deconvolution where successively smaller sub- libraries are prepared and tested to identify individual active members of a combinatorial library. [IUPAC COMBINATORIAL CHEMISTRY] Broader term deconvolution.

linker: Bifunctional chemical moiety attaching compound to solid support or soluble support which can be cleaved to release compounds from the support. Careful choice of linker allows cleavage to be performed under appropriate conditions compatible with the stability of the compound and assay method. [IUPAC COMBINATORIAL CHEMISTRY]

MPS multiple parallel synthesis: See parallel synthesis.

member: a) specific compound which is included in a library; b) the uncharacterized physical product of a library synthesis. [IUPAC COMBINATORIAL CHEMISTRY]

orthogonality: (a) Property of protecting groups or linkers allowing removal, modification, or cleavage of one such without affecting others; (b) pooling strategy whereby library members are incorporated in more than one pool, and are mixed with a different set of other members in each pool. Thus a hit results in two or more active pools with only one member in common.  [IUPAC COMBINATORIAL CHEMISTRY]

parallel synthesis: Strategy whereby sets of discrete compounds are prepared simultaneously in arrays of physically separate reaction vessels or microcompartments without interchange of intermediates during the assembly process. Contrast pool/ split. [IUPAC COMBINATORIAL CHEMISTRY]

pool: (a) A sub-library; (b) process of  combining and mixing library components or sub- libraries. See pool/ split. [IUPAC COMBINATORIAL CHEMISTRY]

pool/split: Also split/ pool; split & mix; divide, couple, recombine; portion/ mix. Strategy for assembly of a combinatorial library. The solid support is divided into portions, each of which is subjected to reaction with a single building block. Pooling of these portions results in a single batch of solid support bearing a mixture of components. Repetition of the divide, couple, recombine processes results in a library where each discrete particle of solid support carries a single library member, and the number of  members is equal to the product of the number of building blocks incorporated at each step (i.e. fully combinatorial) [IUPAC COMBINATORIAL CHEMISTRY]

preformed scaffold: A scaffold which is incorporated into the library as a unit. Compare in situ scaffold. [IUPAC COMBINATORIAL CHEMISTRY] Broader term scaffold.

privileged structure: Substructural feature which confers desirable (often drug- like) properties on compounds containing that feature. Often consists of a semi- rigid scaffold which is able to present multiple hydrophobic residues without undergoing hydrophobic collapse. [IUPAC COMBINATORIAL CHEMISTRY]

random library: See unbiased library. [IUPAC Combinatorial Chemistry]

residue: (a) Portion of a chemical structure which can be identified as being derived from a particular building block, such as the alanine residue in the peptide (b) portion of a building block which is incorporated into the final product but is not part of the scaffold. [IUPAC Combinatorial Chemistry] Compare residue Proteins glossary.

resin: Insoluble polymeric material which allows ready separation from liquid-phase materials by filtration; can be used to carry library members (i.e. solid support) or reagents, or to trap excess reagents or reaction by-products (see scavenger resin) [IUPAC Combinatorial]

SPE: See solid phase extraction.

solid-phase extraction: Method for sample purification whereby either the desired or undesired components of a mixture have preferential affinity for a solid material. Adding the mixture to the solid material then allows facile separation of the desired material by filtration. Related terms sequestration- enabling reagent and scavenger  resin. [IUPAC Combinatorial Chemistry]

solid phase synthesis: Synthesis of compounds on a solid surface such as tiny plastic beads. [Tripos website glossary] http://www.tripos.com/investors/glossary.html

soluble support: An attachment, common to all library members, which renders the library components soluble under conditions for library synthesis, but which can be readily separated from most other soluble components when desired by some simple physical process. This process has been termed liquid- phase chemistry. Examples of soluble supports include linear polymers such as poly(ethylene glycol), dendrimers, or fluorinated compounds which selectively partition into fluorine- rich solvents (see fluorous synthesis). [IUPAC COMBINATORIAL CHEMISTRY]

solution phase: Solution-phase combinatorial approaches have recently become of interest as an alternative drug discovery avenue for lead discovery and optimization.⁴ The key advantages of solution- phase combinatorial approaches include (1) an unlimited number of reactions can be used, therefore, providing maximal structural diversity, (2) an unlimited reaction scale allows for the generation of sufficient quantities of libraries to be derived into different diverse libraries and tested in a broad range of assays, (3) a large excess of reagents and solvents, typically required in solid- phase chemistry, are not needed in solution- phase chemistry, (4) there is no need for linker manipulation, attachment to and detachment from resin; therefore, the reaction sequences for library generation are shorter, (5) soluble intermediates and final products can be obtained directly for purification and assays, (6) it is easy to develop and monitor solution- phase reactions, and (7) it is an efficient way for lead discovery and optimization from single- compound and complex libraries. [Haoyun An "Solution Phase Combinatorial Chemistry: An Overall View" Dept. of Medicinal Chemistry, College of Pharmaceuticals and Biotechnology, Tianjin Univ. China] http://www.tju.edu.cn/eweb/school/pharmtier/abstracts/anhaoyun.htm

sort and combine: Use of directed sorting to facilitate library assembly. Related to pool/ split protocol but more commonly applied to macroscopic solid supports (such as pins and related carriers) where each library member is found on only one, or a small number of carriers. [IUPAC COMBINATORIAL CHEMISTRY]

split/pool: See pool/split

split samples: See under aliquot.

sub-library: See also pool. A subset of a combinatorial library, physically separate from the rest of the library, generally with one or more fixed building block. [IUPAC COMBINATORIAL CHEMISTRY]

tether: See linker.

unbiased library: Library prepared from building blocks and scaffold chosen without bias towards a particular target. [IUPAC COMBINATORIAL CHEMISTRY]