CREDO: a structural interactomics database for drug discovery

Schreyer, Adrian; Blundell, Tom L.

doi:10.1093/database/bat049

Cited by 35 publications

(21 citation statements)

References 41 publications

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“…PICCOLO is currently being updated monthly and can be downloaded and installed locally for free. The original CREDO was frozen in April 2010 and replacement by a new PostgreSQL database [ 81 ]. Residue-based structure interaction fingerprints (SIFts) [ 66 ] where extracted from PICCOLO and CREDO and analysed in various ways including clustering ( cf.…”

Section: Resultsmentioning

confidence: 99%

Polyphony: superposition independent methods for ensemble-based drug discovery

2014

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BackgroundStructure-based drug design is an iterative process, following cycles of structural biology, computer-aided design, synthetic chemistry and bioassay. In favorable circumstances, this process can lead to the structures of hundreds of protein-ligand crystal structures. In addition, molecular dynamics simulations are increasingly being used to further explore the conformational landscape of these complexes. Currently, methods capable of the analysis of ensembles of crystal structures and MD trajectories are limited and usually rely upon least squares superposition of coordinates.ResultsNovel methodologies are described for the analysis of multiple structures of a protein. Statistical approaches that rely upon residue equivalence, but not superposition, are developed. Tasks that can be performed include the identification of hinge regions, allosteric conformational changes and transient binding sites. The approaches are tested on crystal structures of CDK2 and other CMGC protein kinases and a simulation of p38α. Known interaction - conformational change relationships are highlighted but also new ones are revealed. A transient but druggable allosteric pocket in CDK2 is predicted to occur under the CMGC insert. Furthermore, an evolutionarily-conserved conformational link from the location of this pocket, via the αEF-αF loop, to phosphorylation sites on the activation loop is discovered.ConclusionsNew methodologies are described and validated for the superimposition independent conformational analysis of large collections of structures or simulation snapshots of the same protein. The methodologies are encoded in a Python package called Polyphony, which is released as open source to accompany this paper [http://wrpitt.bitbucket.org/polyphony/].

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Section: Resultsmentioning

confidence: 99%

Polyphony: superposition independent methods for ensemble-based drug discovery

2014

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“…Each chain and domain in TOCCATA is annotated using the CREDO database ( 22 ) with information about its binding status to biologically relevant ligands and other chains, and its experimental quality. TOCCATA assigns a ‘quality score’ (Qscore) based on the combination of various measures according to the following equation:

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Section: Methodsmentioning

confidence: 99%

CHOPIN: a web resource for the structural and functional proteome of Mycobacterium tuberculosis

2015

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Tuberculosis kills more than a million people annually and presents increasingly high levels of resistance against current first line drugs. Structural information about Mycobacterium tuberculosis (Mtb) proteins is a valuable asset for the development of novel drugs and for understanding the biology of the bacterium; however, only about 10% of the ∼4000 proteins have had their structures determined experimentally. The CHOPIN database assigns structural domains and generates homology models for 2911 sequences, corresponding to ∼73% of the proteome. A sophisticated pipeline allows multiple models to be created using conformational states characteristic of different oligomeric states and ligand binding, such that the models reflect various functional states of the proteins. Additionally, CHOPIN includes structural analyses of mutations potentially associated with drug resistance. Results are made available at the web interface, which also serves as an automatically updated repository of all published Mtb experimental structures. Its RESTful interface allows direct and flexible access to structures and metadata via intuitive URLs, enabling easy programmatic use of the models.Database URL: http://structure.bioc.cam.ac.uk/chopin

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“…The first version of CREDO 45,46 has been published in 2009, 45 improvements and extensions of the primary concept can be found in the subsequent publication from 2013. 46 Today, CREDOs database stores all intermolecular interactions between all entities in a PDB complex on the atomic level. The current database was built in 2013 from all entries of the PDB except for 96 complexes which were rejected because of an incompatible annotation scheme or incorrect annotated ligands.…”

Section: Credo (Http://maridbioccamacuk/ Credo)mentioning

confidence: 99%

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

Inhester

Rarey

2014

WIREs Comput Mol Sci

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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

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CREDO: a structural interactomics database for drug discovery

Cited by 35 publications

References 41 publications

Polyphony: superposition independent methods for ensemble-based drug discovery

Polyphony: superposition independent methods for ensemble-based drug discovery

CHOPIN: a web resource for the structural and functional proteome of Mycobacterium tuberculosis

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

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