Journal of Computer-Aided Molecular Design

, Volume 19, Issue 3, pp 189–201

A support vector machine approach to classify human cytochrome P450 3A4 inhibitors

  • Jan M. Kriegl
  • Thomas Arnhold
  • Bernd Beck
  • Thomas Fox

DOI: 10.1007/s10822-005-3785-3

Cite this article as:
Kriegl, J.M., Arnhold, T., Beck, B. et al. J Comput Aided Mol Des (2005) 19: 189. doi:10.1007/s10822-005-3785-3


The cytochrome P450 (CYP) enzyme superfamily plays a major role in the metabolism of commercially available drugs. Inhibition of these enzymes by a drug may result in a plasma level increase of another drug, thus leading to unwanted drug–drug interactions when two or more drugs are coadministered. Therefore, fast and reliable in silico methods predicting CYP inhibition from calculated molecular properties are an important tool which can be applied to assess both already synthesized as well as virtual compounds. We have studied the performance of support vector machines (SVMs) to classify compounds according to their potency to inhibit CYP3A4. The data set for model generation consists of more than 1300 structural diverse drug-like research molecules which were divided into training and test sets. The predictive power of SVMs crucially depends on a careful selection of parameters specifying the kernel function and the penalty for misclassifications. In this study we have investigated a procedure to identify a valid set of SVM parameters which is based on a sampling of the parameter space on a regular grid. From this set of parameters, either single SVMs or SVM committees were trained to distinguish between strong and weak inhibitors or to achieve a more realistic three-class assignment, with one class representing medium inhibitors. This workflow was studied for several kernel functions and descriptor sets. All SVM models performed significantly better than PLS-DA models which were generated from the corresponding descriptor sets. As a very promising result, simple two-dimensional (2D) descriptors yield a three-class model which correctly classifies more than 70% of the test set. Our work illustrates that SVMs used in combination with simple 2D descriptors provide a very effective and reliable tool which allows a fast assessment of CYP3A4 inhibition potency in an early in silico filtering process.


ADMEcytochrome P450in silico filtermolecular descriptorQSARsupport vector machine



absorption, distribution, metabolism and excretion


cytochrome P450


partial least squares


discriminant analysis


support vector machine(s)








radial basis function.

Copyright information

© Springer 2005

Authors and Affiliations

  • Jan M. Kriegl
    • 1
  • Thomas Arnhold
    • 2
  • Bernd Beck
    • 1
  • Thomas Fox
    • 1
  1. 1.Computational Chemistry, Department of Lead DiscoveryBoehringer Ingelheim Pharma GmbH & Co. KGBiberachGermany
  2. 2.DDS-DMPK, Department of Drug Discovery Support Boehringer Ingelheim Pharma GmbH & Co. KGBiberachGermany