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  • Review Article
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Chemical database techniques in drug discovery

Nature Reviews Drug Discovery volume 1, pages 220–227 (2002)Cite this article

Key Points

  • Although originally created merely as repositories for compounds synthesized within an organization, chemical databases can now be searched to give novel ideas for lead discovery.

  • The familiar chemical-structure diagrams are not amenable to computational operations such as database searching, so several types of chemical-structure representation have been developed by theoretical chemists for use in computer systems. The predominant form is the atom–bond connection table.

  • A connection table along with two-dimensional coordinates for display is generally sufficient to identify the substance. However, to perform any energy calculations or to determine if the compound has the potential to bind to a receptor or enzyme of interest, three-dimensional coordinates are necessary.

  • Chemical structures differ considerably from other entities that are commonly stored in databases, such as text, and so the various search modes also differ considerably, although some parallels can be drawn.

  • Exact-match searches — which might be performed to find out if a proposed new structure already exists in a database, for example — can be thought of as looking up a complete word in a dictionary.

  • Substructure searches — in which a user picks pieces of a chemical structure and requests that the system return a set of compounds that contain the pieces — are analogous to a wild-carded text search.

  • Similarity searches — which might be performed if a user wants compounds that resemble the compound of interest to a chemist's intuitive thinking but do not necessarily reflect an exact or substructure match — are analogous to a 'sounds like' text search.

  • In pharmacophoric searches, assumptions about which groups of atoms on the small molecule are involved in binding are combined with the spatial relationship of these groups to give a three-dimensional query. Although the process is generally slower than previously mentioned search types, the results provide an indication of whether a set of structures can bind to a receptor or enzyme, and so hits might be very valuable in the drug design process.

  • Molecular docking — placing a series of candidate molecules from a database into the active site of a protein to evaluate how well the compounds might bind to the receptor or enzyme — has become a more popular mode of database searching owing to continual improvement in the quality of the docking and scoring algorithms.

  • Once a database search has been performed, the list of potential molecules for biological testing can be refined by filtering (removing molecules deemed to have unsuitable properties), clustering (grouping similar compounds) and human inspection.

Abstract

Chemical databases are becoming a powerful tool in drug discovery. Database searches based on possible requirements for biological activity can identify compounds that might be suitable for further analysis or indicate novel ways to achieve the desired activity. What considerations are involved in the construction and searching of chemical databases?

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Figure 1: Representations of chemical structure, using the neurotransmitter γ-aminobutyric acid (GABA) as an example.
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Acknowledgements

M. M. would like to thank his colleagues in the scientific architecture group for useful feedback on the manuscript.

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  1. LION bioscience, 9880 Campus Point Drive, San Diego, 92121, California, USA

    Mitchell A. Miller

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FURTHER INFORMATION

CACTVS

ChemIDPlus

ChemWeb

Daylight Chemical Information Systems

Fingerprints — Screening and Similarity

National Cancer Institute Database

SMILES

Glossary

DRUG LIKE

Sharing certain characteristics with other molecules that act as drugs. The set of characteristics — size, shape and solubility in water and organic solvents — varies depending on who is evaluating the molecules.

CYCLIC/ACYCLIC BONDS

If chemical bonds occur in a ring, they are termed 'cyclic'. 'Acyclic bonds' occur in open chain structures.

COUNTERION

A set of one or more bonded atoms, with opposite charge and generally smaller size, that accompanies another charged set of bonded atoms as dictated by the principle of electrical neutrality of substances, solutions and so on.

COMBINATORIAL CHEMISTRY

The generation of large collections, or 'libraries', of compounds by synthesizing all possible combinations of a set of smaller chemical structures.

SEMA NAME

A stereochemical extension of the Morgan algorithm. A compact, canonical representation of a connection table.

SUBSTRUCTURE

One chemical structure is said to be a substructure of another if the first structure can be located within the second. (The second is said to be the superstructure of the first.) All structures are substructures of themselves. A substructure search scans a database for all substructural matches.

CONFORMATIONAL SPACE

The ensemble of three-dimensional shapes that a molecule can adopt without breaking any bonds.

MARKUSH STRUCTURE

Markush structures represent a set of chemical structures as a common core that contains marked substitution sites, and a set of possible fragments for each substitution point. They can be used to represent a set of compounds that are analysed to determine the effect of varying substituents on compound activity; to represent a set of compounds that are produced using combinatorial techniques; to produce a fine-tuned substructure query; or to represent a set of structures in a chemical patent or patent database.

PHARMACOPHORE

The ensemble of steric and electronic features that is necessary to ensure optimal interactions with a specific biological target structure and to trigger (or to block) its biological response.

STEREOCHEMISTRY

The spatial arrangements of atoms in molecules and complexes.

TAUTOMER

One of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

HYDROGEN BOND

A weak attraction (much weaker than a covalent or ionic chemical bond, but much stronger than van der Waals forces) between an oxygen, nitrogen or fluorine atom in one molecule and a hydrogen atom in a neighbouring molecule. Hydrogen-bond donors are groups with electron-hungry hydrogen atoms. Hydrogen-bond acceptors are atoms with electrons to share.

BIT STRING

A contiguous set of characters that consists entirely of 1s and 0s. A bit string can be used to encode a good deal of information in a compact way, and is easily and rapidly interpreted by computer systems.

AND

The combination of two input bits such that the result is 1 if both bits are 1 and 0 otherwise.

LOG P

The octanol/water partition coefficient is the ratio of the solubility of a compound in octanol to its solubility in water (also known as Kow). The logarithm of this partition coefficient is called log P. It provides an estimate of the ability of the compound to pass through a cell membrane.

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Miller, M. Chemical database techniques in drug discovery. Nat Rev Drug Discov 1, 220–227 (2002). https://doi.org/10.1038/nrd745

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