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Drug Metabolism and Disposition Fast Forward
First published on July 1, 2004; DOI: 10.1124/dmd.104.000356

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Received for publication April 27, 2004.
Revised June 15, 2004.
Accepted for publication July 1, 2004.

KOHONEN MAPS FOR PREDICTION OF BINDING TO HUMAN CYTOCHROME P450

Konstantin V Balakin 1, Sean Ekins 2*, Andrey Bugrim 2, Yan A Ivanenkov 3, Dmitry Korolev 3, Yuri V Nikolsky 2, Skorenko V Andrey 3, Andrey A Ivashchenko 3, Nikolay P Savchuk 3, Tatiana Nikolskaya 3

1 Chemical Diveristy Labs 2 GeneGo 3 Chemical Diversity Labs

* Address correspondence to: E-mail: sean{at}genego.com

Abstract

The drug development process utilizes the parallel assessment of activity at a therapeutic target as well as absorption, distribution, metabolism, excretion and toxicity (ADME/TOX) properties of molecules. The development of novel, reliable and inexpensive computational methods for the early assessment of metabolism and toxicity is becoming increasingly an important part of this process. We have used a computational approach for the assessment of drugs and drug-like compounds which bind to the cytochrome P450s (CYPs) with experimentally determined Km values. The physicochemical properties of these compounds were calculated using molecular descriptor software and then analyzed using Kohonen self-organizing maps. This approach was applied to generate a CYP specific classification of nearly 500 drug compounds. We observed statistically significant differences in the molecular properties of low Km molecules for various CYPs and suggest a relationship between 33 of these compounds and their CYP3A4 inhibitory activity. A test set of further CYP3A4 inhibitors was used and 13 out of 15 of these molecules were co-located in the regions of low Km values. This computational approach represents a novel method for use in the generation of metabolism models, enabling the scoring of libraries of compounds for their Km values to numerous CYPs.


Key words: computational models, computer modeling and simulation, CYP3A, cytochrome P450, cytochrome P450 function, structure-activity relationships


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