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Classification of cytochrome p(450) activities using machine learning methods

Hammann, Felix and Gutmann, Heike and Baumann, Ulli and Helma, Christoph and Drewe, Juergen. (2009) Classification of cytochrome p(450) activities using machine learning methods. Molecular pharmaceutics, Vol. 6, H. 6. pp. 1920-1926.

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Official URL: http://edoc.unibas.ch/dok/A5840273

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Abstract

The cytochrome P(450) (CYP) system plays an integral part in the metabolism of drugs and other xenobiotics. Knowledge of the structural features required for interaction with any of the different isoforms of the CYP system is therefore immensely valuable in early drug discovery. In this paper, we focus on three major isoforms (CYP 1A2, CYP 2D6, and CYP 3A4) and present a data set of 335 structurally diverse drug compounds classified for their interaction (as substrate, inhibitor, or any interaction) with these isoforms. We also present machine learning models using a variety of commonly used methods (k-nearest neighbors, decision tree induction using the CHAID and CRT algorithms, random forests, artificial neural networks, and support vector machines using the radial basis function (RBF) and homogeneous polynomials as kernel functions). We discuss the physicochemical features relevant for each end point and compare it to similar studies. Many of these models perform exceptionally well, even with 10-fold cross-validation, yielding corrected classification rates of 81.7 to 91.9% for CYP 1A2, 89.2 to 92.9% for CYP 2D6, and 87.4 to 89.9% for CYP3A4. Our models help in understanding the structural requirements for CYP interactions and can serve as sensitive tools in virtual screenings and lead optimization for toxicological profiles in drug discovery.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Clinical Pharmacology (Drewe)
03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Gastroenterology (Beglinger)
03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
UniBasel Contributors:Gutmann, Heike and Hammann, Felix and Drewe, Jürgen
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Chemical Society
ISSN:1543-8384
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:01 Feb 2013 08:46
Deposited On:01 Feb 2013 08:42

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