Chemical database

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A chemical database is a database specifically designed to store chemical information. This information is about chemical and crystal structures, spectra, reactions and syntheses, and thermophysical data.

Contents

Types of chemical databases

Bioactivity database

Bioactivity databases correlate structures or other chemical information to bioactivity results taken from bioassays in literature, patents, and screening programs.

NameDeveloper(s)Initial release
ScrubChem Jason Bret Harris 2016 [1] [2]
PubChem-BioAssay NIH 2004 [3] [4]
ChEMBL EMBL-EBI 2009 [5]

Chemical structures

Chemical structures are traditionally represented using lines indicating chemical bonds between atoms and drawn on paper (2D structural formulae). While these are ideal visual representations for the chemist, they are unsuitable for computational use and especially for search and storage. Small molecules (also called ligands in drug design applications), are usually represented using lists of atoms and their connections. Large molecules such as proteins are however more compactly represented using the sequences of their amino acid building blocks. Radioactive isotopes are also represented, which is an important attribute for some applications. Large chemical databases for structures are expected to handle the storage and searching of information on millions of molecules taking terabytes of physical memory. [6] [7]

Literature database

Chemical literature databases correlate structures or other chemical information to relevant references such as academic papers or patents. This type of database includes STN, Scifinder, and Reaxys. Links to literature are also included in many databases that focus on chemical characterization.

Crystallographic database

Crystallographic databases store X-ray crystal structure data. Common examples include Protein Data Bank and Cambridge Structural Database.

NMR spectra database

NMR spectra databases correlate chemical structure with NMR data. These databases often include other characterization data such as FTIR and mass spectrometry.

Reactions database

Most chemical databases store information on stable molecules but in databases for reactions also intermediates and temporarily created unstable molecules are stored. Reaction databases contain information about products, educts, and reaction mechanisms.

A popular example that lists chemical reaction data, among others, would be the Beilstein database.

Thermophysical database

Thermophysical data are information about

Chemical structure representation

There are two principal techniques for representing chemical structures in digital databases

These approaches have been refined to allow representation of stereochemical differences and charges as well as special kinds of bonding such as those seen in organo-metallic compounds. The principal advantage of a computer representation is the possibility for increased storage and fast, flexible search.

Substructure

The drug lenalidomide contains substructures isoindoline (red) and glutarimide (blue) Lenalidomide substructures.svg
The drug lenalidomide contains substructures isoindoline (red) and glutarimide (blue)

Chemists can search databases using parts of structures, parts of their IUPAC names as well as based on constraints on properties. Chemical databases are different from other general purpose databases in their support for substructure search, a method to retrieve chemicals matching a pattern of atoms and bonds which a user specifies. This kind of search is achieved by looking for subgraph isomorphism (sometimes also called a monomorphism) and is a widely studied application of graph theory. [8] [9] [10]

Query structures may contain bonding patterns such as "single/aromatic" or "any" to provide flexibility. Similarly, the vertices which in an actual compound would be a specific atom may be replaced with an atom list in the query. Cis–trans isomerism at double bonds is catered for by giving a choice of retrieving only the E form, the Z form, or both. [8] [11]

Conformation

Search by matching 3D conformation of molecules or by specifying spatial constraints is another feature that is particularly of use in drug design. Searches of this kind can be computationally very expensive. Many approximate methods have been proposed, for instance BCUTS, [12] [13] [14] special function representations, moments of inertia, ray-tracing histograms, maximum distance histograms, shape multipoles to name a few. [15] [16] [17] [18] [19]

Examples

Large databases, such as PubChem [11] [20] and ChemSpider, [21] have graphical interfaces for search. The Chemical Abstracts Service provides tools to search the chemical literature and Reaxys supplied by Elsevier covers both chemicals and reaction information, including that originally held in the Beilstein database. [22] PATENTSCOPE makes chemical patents accessible by substructure [23] and Wikipedia's articles describing individual chemicals can also be searched that way. [24]

Suppliers of chemicals as synthesis intermediates or for high-throughput screening routinely provide search interfaces. Currently, the largest database that can be freely searched by the public is the ZINC database, which is claimed to contain over 37 billion commercially available molecules. [25] [26]

Descriptors

All properties of molecules beyond their structure can be split up into either physico-chemical or pharmacological attributes also called descriptors. On top of that, there exist various artificial and more or less standardized naming systems for molecules that supply more or less ambiguous names and synonyms. The IUPAC name is usually a good choice for representing a molecule's structure in a both human-readable and unique string although it becomes unwieldy for larger molecules. Trivial names on the other hand abound with homonyms and synonyms and are therefore a bad choice as a defining database key. While physico-chemical descriptors like molecular weight, (partial) charge, solubility, etc. can mostly be computed directly based on the molecule's structure, pharmacological descriptors can be derived only indirectly using involved multivariate statistics or experimental (screening, bioassay) results. All of those descriptors can for reasons of computational effort be stored along with the molecule's representation and usually are.

Similarity

There is no single definition of molecular similarity, however the concept may be defined according to the application and is often described as an inverse of a measure of distance in descriptor space. Two molecules might be considered more similar for instance if their difference in molecular weights is lower than when compared with others. A variety of other measures could be combined to produce a multi-variate distance measure. Distance measures are often classified into Euclidean measures and non-Euclidean measures depending on whether the triangle inequality holds. Maximum Common Subgraph (MCS) based substructure search [27] (similarity or distance measure) is also very common. MCS is also used for screening drug like compounds by hitting molecules, which share common subgraph (substructure). [28]

Chemicals in the databases may be clustered into groups of 'similar' molecules based on similarities. Both hierarchical and non-hierarchical clustering approaches can be applied to chemical entities with multiple attributes. These attributes or molecular properties may either be determined empirically or computationally derived descriptors. One of the most popular clustering approaches is the Jarvis-Patrick algorithm. [29]

In pharmacologically oriented chemical repositories, similarity is usually defined in terms of the biological effects of compounds (ADME/tox) that can in turn be semiautomatically inferred from similar combinations of physico-chemical descriptors using QSAR methods.

Registration systems

Databases systems for maintaining unique records on chemical compounds are termed as Registration systems. These are often used for chemical indexing, patent systems and industrial databases.

Registration systems usually enforce uniqueness of the chemical represented in the database through the use of unique representations. By applying rules of precedence for the generation of stringified notations, one can obtain unique/'canonical' string representations such as 'canonical SMILES'. Some registration systems such as the CAS system make use of algorithms to generate unique hash codes to achieve the same objective.

A key difference between a registration system and a simple chemical database is the ability to accurately represent that which is known, unknown, and partially known. For example, a chemical database might store a molecule with stereochemistry unspecified, whereas a chemical registry system requires the registrar to specify whether the stereo configuration is unknown, a specific (known) mixture, or racemic. Each of these would be considered a different record in a chemical registry system.

Registration systems also preprocess molecules to avoid considering trivial differences such as differences in halogen ions in chemicals.

An example is the Chemical Abstracts Service (CAS) registration system. See also CAS registry number.

List of Chemical Cartridges

List of Chemical Registration Systems

Web-based

NameDeveloper(s)Initial release
CDD Vault Collaborative Drug Discovery 2018 [40] [41] [42]
Adroit Repository [43] Adroit DI [44] 2023 [45] [46]

Tools

The computational representations are usually made transparent to chemists by graphical display of the data. Data entry is also simplified through the use of chemical structure editors. These editors internally convert the graphical data into computational representations.

There are also numerous algorithms for the interconversion of various formats of representation. An open-source utility for conversion is OpenBabel. These search and conversion algorithms are implemented either within the database system itself or as is now the trend is implemented as external components that fit into standard relational database systems. Both Oracle and PostgreSQL based systems make use of cartridge technology that allows user defined datatypes. These allow the user to make SQL queries with chemical search conditions (For example, a query to search for records having a phenyl ring in their structure represented as a SMILES string in a SMILESCOL column could be

SELECT*FROMCHEMTABLEWHERESMILESCOL.CONTAINS('c1ccccc1')

Algorithms for the conversion of IUPAC names to structure representations and vice versa are also used for extracting structural information from text. However, there are difficulties due to the existence of multiple dialects of IUPAC. Work is on to establish a unique IUPAC standard (See InChI).

See also

Related Research Articles

Cheminformatics refers to the use of physical chemistry theory with computer and information science techniques—so called "in silico" techniques—in application to a range of descriptive and prescriptive problems in the field of chemistry, including in its applications to biology and related molecular fields. Such in silico techniques are used, for example, by pharmaceutical companies and in academic settings to aid and inform the process of drug discovery, for instance in the design of well-defined combinatorial libraries of synthetic compounds, or to assist in structure-based drug design. The methods can also be used in chemical and allied industries, and such fields as environmental science and pharmacology, where chemical processes are involved or studied.

Quantitative structure–activity relationship models are regression or classification models used in the chemical and biological sciences and engineering. Like other regression models, QSAR regression models relate a set of "predictor" variables (X) to the potency of the response variable (Y), while classification QSAR models relate the predictor variables to a categorical value of the response variable.

A molecule editor is a computer program for creating and modifying representations of chemical structures.

<span class="mw-page-title-main">Chemical space</span>

Chemical space is a concept in cheminformatics referring to the property space spanned by all possible molecules and chemical compounds adhering to a given set of construction principles and boundary conditions. It contains millions of compounds which are readily accessible and available to researchers. It is a library used in the method of molecular docking.

<span class="mw-page-title-main">Docking (molecular)</span> Prediction method in molecular modeling

In the field of molecular modeling, docking is a method which predicts the preferred orientation of one molecule to a second when a ligand and a target are bound to each other to form a stable complex. Knowledge of the preferred orientation in turn may be used to predict the strength of association or binding affinity between two molecules using, for example, scoring functions.

PubChem is a database of chemical molecules and their activities against biological assays. The system is maintained by the National Center for Biotechnology Information (NCBI), a component of the National Library of Medicine, which is part of the United States National Institutes of Health (NIH). PubChem can be accessed for free through a web user interface. Millions of compound structures and descriptive datasets can be freely downloaded via FTP. PubChem contains multiple substance descriptions and small molecules with fewer than 100 atoms and 1,000 bonds. More than 80 database vendors contribute to the growing PubChem database.

A structural analog, also known as a chemical analog or simply an analog, is a compound having a structure similar to that of another compound, but differing from it in respect to a certain component.

Molecule mining is the process of data mining, or extracting and discovering patterns, as applied to molecules. Since molecules may be represented by molecular graphs, this is strongly related to graph mining and structured data mining. The main problem is how to represent molecules while discriminating the data instances. One way to do this is chemical similarity metrics, which has a long tradition in the field of cheminformatics.

MDL Information Systems, Inc. was a provider of R&D informatics products for the life sciences and chemicals industries. The company was launched as a computer-aided drug design firm in January 1978 in Hayward, California. The company was acquired by Symyx Technologies, Inc. in 2007. Subsequently Accelrys merged with Symyx. The Accelrys name was retained for the combined company. In 2014 Accelrys was acquired by Dassault Systemes. The Accelrys business unit was renamed BIOVIA.

<span class="mw-page-title-main">ISIS/Draw</span>

ISIS/Draw was a chemical structure drawing program developed by MDL Information Systems. It introduced a number of file formats for the storage of chemical information that have become industry standards.

<span class="mw-page-title-main">Substructure search</span> Method of finding chemicals in a database

Substructure search (SSS) is a method to retrieve from a database only those chemicals matching a pattern of atoms and bonds which a user specifies. It is an application of graph theory, specifically subgraph matching in which the query is a hydrogen-depleted molecular graph. The mathematical foundations for the method were laid in the 1870s, when it was suggested that chemical structure drawings were equivalent to graphs with atoms as vertices and bonds as edges. SSS is now a standard part of cheminformatics and is widely used by pharmaceutical chemists in drug discovery.

<span class="mw-page-title-main">Virtual screening</span>

Virtual screening (VS) is a computational technique used in drug discovery to search libraries of small molecules in order to identify those structures which are most likely to bind to a drug target, typically a protein receptor or enzyme.

ChemSpider is a freely accessible online database of chemicals owned by the Royal Society of Chemistry. It contains information on more than 100 million molecules from over 270 data sources, each of them receiving a unique identifier called ChemSpider Identifier.

Druglikeness is a qualitative concept used in drug design for how "druglike" a substance is with respect to factors like bioavailability. It is estimated from the molecular structure before the substance is even synthesized and tested. A druglike molecule has properties such as:

SMILES arbitrary target specification (SMARTS) is a language for specifying substructural patterns in molecules. The SMARTS line notation is expressive and allows extremely precise and transparent substructural specification and atom typing.

<span class="mw-page-title-main">Chemical similarity</span> Chemical term

Chemical similarity refers to the similarity of chemical elements, molecules or chemical compounds with respect to either structural or functional qualities, i.e. the effect that the chemical compound has on reaction partners in inorganic or biological settings. Biological effects and thus also similarity of effects are usually quantified using the biological activity of a compound. In general terms, function can be related to the chemical activity of compounds.

<span class="mw-page-title-main">Antony John Williams</span> British chemist

Antony John Williams is a British chemist and expert in the fields of both nuclear magnetic resonance (NMR) spectroscopy and cheminformatics at the United States Environmental Protection Agency. He is the founder of the ChemSpider website that was purchased by the Royal Society of Chemistry in May 2009. He is a science blogger and an author.

Matched molecular pair analysis (MMPA) is a method in cheminformatics that compares the properties of two molecules that differ only by a single chemical transformation, such as the substitution of a hydrogen atom by a chlorine one. Such pairs of compounds are known as matched molecular pairs (MMP). Because the structural difference between the two molecules is small, any experimentally observed change in a physical or biological property between the matched molecular pair can more easily be interpreted. The term was first coined by Kenny and Sadowski in the book Chemoinformatics in Drug Discovery.

A chemical graph generator is a software package to generate computer representations of chemical structures adhering to certain boundary conditions. The development of such software packages is a research topic of cheminformatics. Chemical graph generators are used in areas such as virtual library generation in drug design, in molecular design with specified properties, called inverse QSAR/QSPR, as well as in organic synthesis design, retrosynthesis or in systems for computer-assisted structure elucidation (CASE). CASE systems again have regained interest for the structure elucidation of unknowns in computational metabolomics, a current area of computational biology.

SIRIUS is a Java-based open-source software for the identification of small molecules from fragmentation mass spectrometry data without the use of spectral libraries. It combines the analysis of isotope patterns in MS1 spectra with the analysis of fragmentation patterns in MS2 spectra. SIRIUS is the umbrella application comprising CSI:FingerID, CANOPUS, COSMIC and ZODIAC.

References

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