Chemical library
Encyclopedia
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.
high-throughput screening
, it is desirable to screen a drug target against a selection of chemicals that try to take advantage of as much of the appropriate chemical space
as possible. The chemical space
of all possible chemical structure
s is extraordinarily large. Most stored chemical libraries do not typically have a fully represented or sampled chemical space mostly because of storage and cost concerns. However, since many molecular interactions cannot be predicted, the wider the chemical space that is sampled by the chemical library, the better the chance that high-throughput screening
will find an "hit" -- a chemical with an appropriate interaction in a biological model that might be developed into a drug.
An example of a chemical library in drug discovery would be a series of chemicals known to inhibit kinases, or in industrial processes, a series of catalysts known to polymerize resins.
process for instance, a wide range of organic chemicals are needed to test against models of disease in high-throughput screening
. Therefore, most of the chemical synthesis needed to generate chemical libraries in drug discovery
is based on organic chemistry
. A company that is interested in screening for kinase
inhibitors in cancer
may limit their chemical libraries and synthesis to just those types of chemicals known to have affinity for ATP binding sites or allosteric sites.
Generally, however, most chemical libraries focus on large groups of varied organic chemical series where an organic chemist can make many variations on the same molecular scaffold or molecular backbone. Sometimes chemicals can be purchased from outside vendors as well and included into an internal chemical library.
and medicinal chemistry
. The method of chemical library generation usually depends on the project and there are many factors to consider when using rational methods to select screening compounds. Typically, a range of chemicals is screened against a particular drug target or disease model, and the preliminary "hits", or chemicals that show the desired activity, are re-screened to verify their activity. Once they are qualified as a "hit" by their repeatability and activity, these particular chemicals are registered and analysed. Commonalities among the different chemical groups are studied as they are often reflective of a particular chemical subspace. Additional chemistry work may be needed to further optimize the chemical library in the active portion of the subspace. When it is needed, more synthesis is completed to extend out the chemical library in that particular subspace by generating more compounds that are very similar to the original hits. This new selection of compounds within this narrow range are further screened and then taken on to more sophisticated models for further validation in the Drug Discovery Hit to Lead
process.
mostly because of storage and cost concerns.
Because of the expense and effort involved in chemical synthesis, the chemicals must be correctly stored and banked away for later use to prevent early degradation. Each chemical has a particular shelf life and storage requirement and in a good-sized chemical library, there is a timetable by which library chemicals are disposed of and replaced on a regular basis. Some chemicals are fairly unstable, radioactive, volatile or flammable and must be stored under careful conditions in accordance with safety standards such as OSHA
.
Most chemical libraries are managed with information technologies such as barcoding
and relational database
s. Additionally, robotics
are necessary to fetch compounds in larger chemical libraries.
Because a chemical library's individual entries can easily reach up into the millions of compounds, the management of even modest-sized chemical libraries can be a full-time endeavor. Compound management
is one such field that attempts to manage and upkeep these chemical libraries as well as maximizing safety and effectiveness in their management.
High-throughput screening
High-throughput screening is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry. Using robotics, data processing and control software, liquid handling devices, and sensitive detectors, High-Throughput Screening allows a...
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
Chemical structure
A chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...
, purity, quantity, and physiochemical characteristics of the compound.
Purpose
In drug discoveryDrug discovery
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered or designed.In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery...
high-throughput screening
High-throughput screening
High-throughput screening is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry. Using robotics, data processing and control software, liquid handling devices, and sensitive detectors, High-Throughput Screening allows a...
, it is desirable to screen a drug target against a selection of chemicals that try to take advantage of as much of the appropriate chemical space
Chemical space
Chemical space is the space spanned by all possible molecules and chemical compounds – that is, all stoichiometric combinations of electrons and atomic nuclei, in all possible topology isomers. Chemical reactions allow us to move in chemical space...
as possible. The chemical space
Chemical space
Chemical space is the space spanned by all possible molecules and chemical compounds – that is, all stoichiometric combinations of electrons and atomic nuclei, in all possible topology isomers. Chemical reactions allow us to move in chemical space...
of all possible chemical structure
Chemical structure
A chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...
s is extraordinarily large. Most stored chemical libraries do not typically have a fully represented or sampled chemical space mostly because of storage and cost concerns. However, since many molecular interactions cannot be predicted, the wider the chemical space that is sampled by the chemical library, the better the chance that high-throughput screening
High-throughput screening
High-throughput screening is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry. Using robotics, data processing and control software, liquid handling devices, and sensitive detectors, High-Throughput Screening allows a...
will find an "hit" -- a chemical with an appropriate interaction in a biological model that might be developed into a drug.
An example of a chemical library in drug discovery would be a series of chemicals known to inhibit kinases, or in industrial processes, a series of catalysts known to polymerize resins.
Generation of chemical libraries
Chemical libraries are usually generated for a specific goals and larger chemical libraries could be made of several groups of smaller libraries stored in the same location. In the drug discoveryDrug discovery
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered or designed.In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery...
process for instance, a wide range of organic chemicals are needed to test against models of disease in high-throughput screening
High-throughput screening
High-throughput screening is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry. Using robotics, data processing and control software, liquid handling devices, and sensitive detectors, High-Throughput Screening allows a...
. Therefore, most of the chemical synthesis needed to generate chemical libraries in drug discovery
Drug discovery
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered or designed.In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery...
is based on organic chemistry
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
. A company that is interested in screening for kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
inhibitors in cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
may limit their chemical libraries and synthesis to just those types of chemicals known to have affinity for ATP binding sites or allosteric sites.
Generally, however, most chemical libraries focus on large groups of varied organic chemical series where an organic chemist can make many variations on the same molecular scaffold or molecular backbone. Sometimes chemicals can be purchased from outside vendors as well and included into an internal chemical library.
Design and optimization of chemical libraries
Chemical libraries are usually designed by chemists and chemoinformatics scientists and synthesized by organic chemistryOrganic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
and medicinal chemistry
Medicinal 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 it is involved with design, chemical synthesis and development for market of pharmaceutical...
. The method of chemical library generation usually depends on the project and there are many factors to consider when using rational methods to select screening compounds. Typically, a range of chemicals is screened against a particular drug target or disease model, and the preliminary "hits", or chemicals that show the desired activity, are re-screened to verify their activity. Once they are qualified as a "hit" by their repeatability and activity, these particular chemicals are registered and analysed. Commonalities among the different chemical groups are studied as they are often reflective of a particular chemical subspace. Additional chemistry work may be needed to further optimize the chemical library in the active portion of the subspace. When it is needed, more synthesis is completed to extend out the chemical library in that particular subspace by generating more compounds that are very similar to the original hits. This new selection of compounds within this narrow range are further screened and then taken on to more sophisticated models for further validation in the Drug Discovery Hit to Lead
Drug discovery hit to lead
Early drug discovery involves several phases from target identification to preclinical development. The identification of small molecule modulators of protein function and the process of transforming these into high-content lead series are key activities in modern drug discovery. The Hit-to-Lead...
process.
Storage and management
The "chemical space" of all possible organic chemicals is large and increases exponentially with the size of the molecule. Most chemical libraries do not typically have a fully represented chemical spaceChemical space
Chemical space is the space spanned by all possible molecules and chemical compounds – that is, all stoichiometric combinations of electrons and atomic nuclei, in all possible topology isomers. Chemical reactions allow us to move in chemical space...
mostly because of storage and cost concerns.
Because of the expense and effort involved in chemical synthesis, the chemicals must be correctly stored and banked away for later use to prevent early degradation. Each chemical has a particular shelf life and storage requirement and in a good-sized chemical library, there is a timetable by which library chemicals are disposed of and replaced on a regular basis. Some chemicals are fairly unstable, radioactive, volatile or flammable and must be stored under careful conditions in accordance with safety standards such as OSHA
Occupational Safety and Health Administration
The United States Occupational Safety and Health Administration is an agency of the United States Department of Labor. It was created by Congress of the United States under the Occupational Safety and Health Act, signed by President Richard M. Nixon, on December 29, 1970...
.
Most chemical libraries are managed with information technologies such as barcoding
Barcode
A barcode is an optical machine-readable representation of data, which shows data about the object to which it attaches. Originally barcodes represented data by varying the widths and spacings of parallel lines, and may be referred to as linear or 1 dimensional . Later they evolved into rectangles,...
and relational database
Relational database
A relational database is a database that conforms to relational model theory. The software used in a relational database is called a relational database management system . Colloquial use of the term "relational database" may refer to the RDBMS software, or the relational database itself...
s. Additionally, robotics
Robotics
Robotics is the branch of technology that deals with the design, construction, operation, structural disposition, manufacture and application of robots...
are necessary to fetch compounds in larger chemical libraries.
Because a chemical library's individual entries can easily reach up into the millions of compounds, the management of even modest-sized chemical libraries can be a full-time endeavor. Compound management
Compound management
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...
is one such field that attempts to manage and upkeep these chemical libraries as well as maximizing safety and effectiveness in their management.
Further reading
- Ian Yates. Compound Management comes of age. Drug Discovery World Spring 2003 p35-43
- Archer JR. History, evolution, and trends in compound management for high-throughput screening. Assay Drug Dev Technol. 2004 Dec;2(6):675-81
- Casey R. Designing Chemical Compound Libraries for Drug Discovery. Business Intelligence Network December 1, 2005.
- GLARE - A free open source software for combinatorial library design.
- Examples of Chemical libraries for Drug Discovery