Novel Application of 2D and 3D-Similarity Searches To Identify Substrates among Cytochrome P450 2C9, 2D6, and 3A4

Novel Application of 2D and 3D-Similarity Searches To Identify Substrates among Cytochrome P450 2C9, 2D6, and 3A4

Cytochrome P450 (CYP450) is a class of enzymes where the substrate identification is particularly important to know. It would help medicinal chemists to design drugs with lower side effects due to drug−drug interactions and to extensive genetic polymorphism. Herein, we discuss the application of the...

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Bibliographic Details
Published in:Journal of chemical information and modeling Vol. 50; no. 1; pp. 97 - 109
Main Authors: Freitas, R. F, Bauab, R. L, Montanari, C. A
Format: Journal Article
Language:English
Published: Washington, DC American Chemical Society 25-01-2010
Subjects:
Applied sciences
Area Under Curve
Biological and medical sciences
Chemical compounds
Computational Chemistry
Computer science; control theory; systems
Cytochrome P-450 CYP2D6 - metabolism
Cytochrome P-450 CYP3A - metabolism
Cytochrome P-450 Enzyme System - metabolism
Drug Discovery - methods
Enzymes
Exact sciences and technology
General pharmacology
Information systems. Data bases
Isoenzymes - metabolism
Medical sciences
Memory organisation. Data processing
Molecular structure
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Polymorphism
Protein Binding
Reproducibility of Results
ROC Curve
Software
Validity
Cytochrome
Validation
Nearest neighbour
Pharmaceutical technology
Hierarchical classification
Enzyme
Pharmacology
Search algorithm
Structure activity relation
Edge effect
Scoring credit
Drug interaction
Polymorphism
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Summary:Cytochrome P450 (CYP450) is a class of enzymes where the substrate identification is particularly important to know. It would help medicinal chemists to design drugs with lower side effects due to drug−drug interactions and to extensive genetic polymorphism. Herein, we discuss the application of the 2D and 3D-similarity searches in identifying reference structures with higher capacity to retrieve substrates of three important CYP enzymes (CYP2C9, CYP2D6, and CYP3A4). On the basis of the complementarities of multiple reference structures selected by different similarity search methods, we proposed the fusion of their individual Tanimoto scores into a consensus Tanimoto score (T consensus). Using this new score, true positive rates of 63% (CYP2C9) and 81% (CYP2D6) were achieved with false positive rates of 4% for the CYP2C9−CYP2D6 data set. Extended similarity searches were carried out on a validation data set, and the results showed that by using the T consensus score, not only the area of a ROC graph increased, but also more substrates were recovered at the beginning of a ranked list.
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SourceType-Scholarly Journals-1
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ISSN:1549-9596
1549-960X
DOI:10.1021/ci900074t