Compound management

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Drug discovery depends on methods by which many different chemicals are assayed for their activity. These chemicals are stored as physical quantities in a chemical library or libraries which are often assembled from both outside vendors and internal chemical synthesis efforts. These chemical libraries are used in high-throughput screening in the drug discovery hit to lead process. [1]

Drug discovery the process by which new candidate medications are discovered

In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered.

A chemical library or compound library is a collection of stored chemicals usually used ultimately in high-throughput screening or industrial manufacture. The chemical library can consist in simple terms of a series of stored chemicals. Each chemical has associated information stored in some kind of database with information such as the chemical structure, purity, quantity, and physiochemical characteristics of the compound.

Chemical synthesis is the artificial execution of useful chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In modern laboratory uses, the process is reproducible, reliable, and established to work the same in multiple laboratories.

Contents

The chemical libraries in larger pharmaceutical companies are a critical part of the discovery process. These chemicals are stored in environmentally controlled conditions in small or large containers, often labeled with codes that pass back into a database. Each chemical in the storage bank must be monitored for shelf life, quantity, purity and other parameters, and its banked location. In some companies, the compounds can also include biological compounds, such as purified proteins or nucleic acids. The management of these chemical libraries, including renewal of outdated chemicals, databases containing the information, robotics often involved in fetching chemicals, and quality control of the storage environment is called Compound Management or Compound Control. Compound Management is often a significant expense, as well as career for one or more individuals who manage a chemical library at a research site. [2]

There are many books and journal articles devoted entirely or in part to compound management. [3] It has become a critical technological component for high-throughput screening and chemical genomics. There are great challenges to be faced in the necessity of compound management, which are being surmounted by concerted efforts in the public and private domain. [4] In 2008, authors at the National Institutes of Health's Chemical Genomics Center have released a paper showing the necessity of a highly automated, reliable and parallel compound management platform, in order to serve over 200,000 different compounds. [5]

National Institutes of Health Medical research organization in the United States

The National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late 1870s, and is now part of the United States Department of Health and Human Services. The majority of NIH facilities are located in Bethesda, Maryland. The NIH conducts its own scientific research through its Intramural Research Program (IRP) and provides major biomedical research funding to non-NIH research facilities through its Extramural Research Program.

In short, Compound Management requires inventory control of small molecules and biologics needed for assays and experiments, especially in high-throughput screening. It utilizes knowledge of chemistry, robotics, biology, and database management. The manager must also be acutely aware of safety standards in the handling and storing of radioactive, volatile, flammable and unstable compounds. Often, in large pharmaceutical companies, the chemical and biological compounds contained in compound libraries can number in the millions, making compound management and compound control important contributors to research and drug discovery.

High-throughput screening Drug discovery experimental technique

High-throughput screening (HTS) is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry. Using robotics, data processing/control software, liquid handling devices, and sensitive detectors, high-throughput screening allows a researcher to quickly conduct millions of chemical, genetic, or pharmacological tests. Through this process one can rapidly identify active compounds, antibodies, or genes that modulate a particular biomolecular pathway. The results of these experiments provide starting points for drug design and for understanding the noninteraction or role of a particular location.

Chemistry scientific discipline

Chemistry is the scientific discipline involved with elements and compounds composed of atoms, molecules and ions: their composition, structure, properties, behavior and the changes they undergo during a reaction with other substances.

Robotics Design, construction, operation, and application of robots

Robotics is an interdisciplinary branch of engineering and science that includes mechanical engineering, electronic engineering, information engineering, computer science, and others. Robotics deals with the design, construction, operation, and use of robots, as well as computer systems for their control, sensory feedback, and information processing.

Outsourcing

Because of the significant expenses and infrastructure required for accurate compound management (space requirements, robotics, IT support, analytical support, etc.) many companies choose to outsource this function to a company that specializes in this arena. It is important to work with a company that has significant experience in compound management due to the complexity of tracking not only inventory data, but also compound location, storage conditions, and compound integrity. This experience also is of paramount importance when knowing how to appropriately deal with the wide array of materials handled including, solids, liquids, volatile materials, sticky solids, oils, and gums as well as hazardous, flammable, hygroscopic and toxic compounds.

Customers can specify not only the quantity of material but also the exact vial and cap or plate for their specific application. The service provides enormous savings from a time perspective as researchers do not spend their valuable time on weighing hundreds of compounds or getting them into the correct format for their assay. It also dramatically reduces disposal costs since the exact amount of material required can be ordered rather than needing to order e.g. 100 g of material when only 0.1 g is needed for the experiment.

The high throughput analytical chemistry component of the company allows rapid validation that compounds are the correct material at the desired purity. While controlled storage conditions minimize degradation, customers may use this service to validate that the material they sent to outsourcing partner originally was correct and pure. Subsequently the service allows re-evaluation of compounds that may have decomposed during long term storage. The purification services complement the analytical services by allowing cost effective, environmentally friendly recovery of partially degraded reactive intermediates and HTS compounds at a fraction of the cost of synthesizing or purchasing these materials.

Analytical chemistry study of the separation, identification, and quantification of the chemical components of materials

Analytical chemistry studies and uses instruments and methods used to separate, identify, and quantify matter. In practice, separation, identification or quantification may constitute the entire analysis or be combined with another method. Separation isolates analytes. Qualitative analysis identifies analytes, while quantitative analysis determines the numerical amount or concentration.

Conferences

There are several conferences related to compound management. The best known is Compound Management & Integrity [6] although many chemistry and pharmaceutical conferences include talks or specific sections on the topic.

Related Research Articles

Reagent substance or compound that is added to a system in order to bring about a chemical reaction, or added to see if a reaction occurs

A reagent is a substance or compound added to a system to cause a chemical reaction, or added to test if a reaction occurs. The terms reactant and reagent are often used interchangeably—however, a reactant is more specifically a substance consumed in the course of a chemical reaction. Solvents, though involved in the reaction, are usually not called reactants. Similarly, catalysts are not consumed by the reaction, so they are not reactants. In biochemistry, especially in connection with enzyme-catalyzed reactions, the reactants are commonly called substrates.

Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder or brown recluse spider.

An assay is an investigative (analytic) procedure in laboratory medicine, pharmacology, environmental biology and molecular biology for qualitatively assessing or quantitatively measuring the presence, amount, or functional activity of a target entity. The analyte can be a drug, a biochemical substance, or a cell in an organism or organic sample. The measured entity is generally called the analyte, the measurand or the target of the assay. The assay usually aims to measure an intensive property of the analyte and express it in the relevant measurement unit.

Cheminformatics is the use of computer and informational techniques applied to a range of problems in the field of chemistry. These in silico techniques are used, for example, in pharmaceutical companies and academic settings in the process of drug discovery. These methods can also be used in chemical and allied industries in various other forms.

Laboratory robotics

Laboratory robotics is the act of using robots in biology or chemistry labs. For example, pharmaceutical companies employ robots to move biological or chemical samples around to synthesize novel chemical entities or to test pharmaceutical value of existing chemical matter. Advanced laboratory robotics can be used to completely automate the process of science, as in the Robot Scientist project.

Medicinal chemistry scientific branch of pharmaceutical chemistry

Medicinal chemistry and pharmaceutical chemistry are disciplines at the intersection of chemistry, especially synthetic organic chemistry, and pharmacology and various other biological specialties, where they are involved with design, chemical synthesis and development for market of pharmaceutical agents, or bio-active molecules (drugs).

Chemogenomics

Chemogenomics, or chemical genomics, is the systematic screening of targeted chemical libraries of small molecules against individual drug target families with the ultimate goal of identification of novel drugs and drug targets. Typically some members of a target library have been well characterized where both the function has been determined and compounds that modulate the function of those targets have been identified. Other members of the target family may have unknown function with no known ligands and hence are classified as orphan receptors. By identifying screening hits that modulate the activity of the less well characterized members of the target family, the function of these novel targets can be elucidated. Furthermore, the hits for these targets can be used as a starting point for drug discovery. The completion of the human genome project has provided an abundance of potential targets for therapeutic intervention. Chemogenomics strives to study the intersection of all possible drugs on all of these potential targets.

Chemical compound microarray

A chemical compound microarray is a collection of organic chemical compounds spotted on a solid surface, such as glass and plastic. This microarray format is very similar to DNA microarray, protein microarray and antibody microarray. In chemical genetics research, they are routinely used for searching proteins that bind with specific chemical compounds, and in general drug discovery research, they provide a multiplex way to search potential drugs for therapeutic targets.

High-content screening (HCS), also known as high-content analysis (HCA) or cellomics, is a method that is used in biological research and drug discovery to identify substances such as small molecules, peptides, or RNAi that alter the phenotype of a cell in a desired manner. Hence high content screening is a type of phenotypic screen conducted in cells involving the analysis of whole cells or components of cells with simultaneous readout of several parameters. HCS is related to high-throughput screening (HTS), in which thousands of compounds are tested in parallel for their activity in one or more biological assays, but involves assays of more complex cellular phenotypes as outputs. Phenotypic changes may include increases or decreases in the production of cellular products such as proteins and/or changes in the morphology of the cell. Hence HCA typically involves automated microscopy and image analysis. Unlike high-content analysis, high-content screening implies a level of throughput which is why the term "screening" differentiates HCS from HCA, which may be high in content but low in throughput.

Hit to lead (H2L) also known as lead generation is a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds. These lead compounds undergo more extensive optimization in a subsequent step of drug discovery called lead optimization (LO). The drug discovery process generally follows the following path that includes a hit to lead stage:

A lead compound in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, but may nevertheless have suboptimal structure that requires modification to fit better to the target; lead drugs offer the prospect of being followed by back-up compounds. Its chemical structure serves as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters. Furthermore, newly invented pharmacologically active moieties may have poor druglikeness and may require chemical modification to become drug-like enough to be tested biologically or clinically.

High throughput cell biology is the use of automation equipment with classical cell biology techniques to address biological questions that are otherwise unattainable using conventional methods. It may incorporate techniques from optics, chemistry, biology or image analysis to permit rapid, highly parallel research into how cells function, interact with each other and how pathogens exploit them in disease.

Institut Pasteur Korea is an infectious disease-focused research institute located in Gyeonggi Province, Rep. of Korea. Its mission is to identify novel molecular targets and discover small molecules by utilizing its proprietary platforms to diagnose, treat and address serious unmet global public health needs.

Pan-assay interference compounds (PAINS) are chemical compounds that often give false positive results in high-throughput screens. PAINS tend to react nonspecifically with numerous biological targets rather than specifically affecting one desired target. A number of disruptive functional groups are shared by many PAINS.

Aurora Biosciences

Aurora Biosciences was a biotechnology company founded in 1995 in San Diego to commercialize fluorescence assays based on Roger Y. Tsien's discoveries concerning green fluorescent protein and its uses in basic research - work for which Tsien eventually won the 2008 Nobel Prize in chemistry along with two other chemists. Aurora was formed at a time when established pharmaceutical companies were seeking to harness the fruits of the Human Genome Project, which had overwhelmed them with potential drug targets, and the explosion of new research tools enabled by biotechnology, as well as revolutions in chemistry that allowed many more, and many more kinds, of potential drugs to be made.

The European Lead Factory is a public-private partnership that aims to accelerate early drug discovery in Europe. The European Lead Factory is funded by the Innovative Medicines Initiative and consists of a pan-European consortium that includes 7 pharmaceutical companies as well as partners from academia and small and medium-sized enterprises (SMEs).

Fluorescence polarization immunoassay

Fluorescence polarization immunoassay (FPIA) is a class of in vitro biochemical test used for rapid detection of antibody or antigen in sample. FPIA is a competitive homogenous assay, that consists of a simple prepare and read method, without the requirement of separation or washing steps.

References

  1. ↑ J. Richard Archer (1 December 2004). "History, Evolution, and Trends in Compound Management for High Throughput Screening". ASSAY and Drug Development Technologies. 2 (6): 675–681. doi:10.1089/adt.2004.2.675. PMID   15674025.
  2. ↑ Ian Yates (Spring 2003). "Compound Management Comes of Age" (PDF). Drug Discovery World: 35–42. Archived from the original (PDF) on 11 May 2008. Retrieved 10 November 2008.
  3. ↑ Jeffrey S. Handen (2005). "Compound Management". Industrialization of Drug Discovery. CRC Press. ISBN   9780824723910.
  4. ↑ R. Wedin (January–February 1999). "Taming the monster haystack: The challenge of compound management". Modern Drug Discovery. 2: 47–53.
  5. ↑ Adam Yasgar; et al. (April 2008). "Compound Management for Quantitative High-Throughput Screening". JALA Charlottesv Va. 13 (2): 79–89. doi:10.1016/j.jala.2007.12.004. PMC   2390859 . PMID   18496600.
  6. ↑ Conference: Compound Management & Integrity 2009 Archived 25 December 2008 at the Wayback Machine
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