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WIREs Comput Mol Sci
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Protein–ligand interaction databases: advanced tools to mine activity data and interactions on a structural level

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The formation of molecular complexes between proteins and small organic substances is a fundamental concept of life. Biochemical experiments from X‐ray crystallography to isothermal titration calorimetry (ITC) are applied in large‐scale providing data for the analysis of the structural foundations of binding affinity. In recent years, several, mostly publically available databases emerged containing affinity data and structural information. These databases are central for the construction of complex models describing interaction geometries and correlate structural features to the strength of binding. Binding affinity databases reflect the knowledge of affinity measurements from many sources, mostly scientific and patent literature. A critical aspect is the data quality, which is affected by transcription errors during database construction as well as experimental uncertainties. The Protein Data Bank (PDB) is the central resource for macromolecular biological structures containing nearly 100,000 data entries today. Sophisticated geometric databases have been constructed based on this allowing for complex queries about the spatial arrangement of functional groups and their interactions. For scientists working in molecular design like medicinal chemists, access to this information can substantially support the process of creating new molecular entities specifically interacting with proteins of interest. WIREs Comput Mol Sci 2014, 4:562–575. doi: 10.1002/wcms.1192 This article is categorized under: Structure and Mechanism > Molecular Structures Computer and Information Science > Chemoinformatics Computer and Information Science > Databases and Expert Systems
Example user query possible in Relibase. A hydroxyphenyl group is defined as part of the ligand. An aromatic ring and a guanidine group are defined as parts of the protein. Distance constrains are shown in green dashed lines, and angle constrains are indicated in purple. Ring normals can be defined in the Relibase graphical user interface and are shown in orange here.
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Example user query possible in PROLIX. A hydroxyphenyl group is defined as part of the ligand. Interactions between atoms of the ligand and amino acids are shown with blue dashed lines. Distance constraints are depicted with green dashed lines. Distance constraints between amino acids either refer to the distance between their Cα atoms or between their closest atoms. Arginine and phenylalanine should be present in the binding site, indicated by their names. The absence of an amino acid is defined by a crossed name, in this case glutamine.
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Example user query for PRDB. Using the ligand substructure search, all ligands containing a hydroxyphenyl group can be searched. Distance constraints are shown with green dashed lines between the corresponding atoms. Angle constrains can be added for the relative position of two ring systems. This angle, shown in purple, refers to the angle between the two ring normals, depicted in orange. Distance constraints between residues can only be stated as distances between their Cα atoms.
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Example user query possible in PDBeMotif. The query consists of two search elements: A hydroxyphenyl group as ligand substructure and a protein sequence consisting of phenylalanine—any amino acid (x)—arginine. Two interactions between both search elements are defined: (1) a hydrogen bond between the ligand's oxygen and the arginin's NH1, shown in blue. (2) a plane–plane interaction between the ligand's and the phenylalanine's aromatic rings, depicted in blue. The plane–plane interaction can further be specified with an angle between both ring normals. The angle constraint is shown in purple, while the ring normas are depicted in orange.
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Computer and Information Science > Chemoinformatics
Structure and Mechanism > Molecular Structures

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