Trainable structure-activity relationship model for virtual screening of CYP3A4 inhibition

J Comput Aided Mol Des. 2010 Nov;24(11):891-906. doi: 10.1007/s10822-010-9381-1. Epub 2010 Sep 1.


A new structure-activity relationship model predicting the probability for a compound to inhibit human cytochrome P450 3A4 has been developed using data for >800 compounds from various literature sources and tested on PubChem screening data. Novel GALAS (Global, Adjusted Locally According to Similarity) modeling methodology has been used, which is a combination of baseline global QSAR model and local similarity based corrections. GALAS modeling method allows forecasting the reliability of prediction thus defining the model applicability domain. For compounds within this domain the statistical results of the final model approach the data consistency between experimental data from literature and PubChem datasets with the overall accuracy of 89%. However, the original model is applicable only for less than a half of PubChem database. Since the similarity correction procedure of GALAS modeling method allows straightforward model training, the possibility to expand the applicability domain has been investigated. Experimental data from PubChem dataset served as an example of in-house high-throughput screening data. The model successfully adapted itself to both data classified using the same and different IC₅₀ threshold compared with the training set. In addition, adjustment of the CYP3A4 inhibition model to compounds with a novel chemical scaffold has been demonstrated. The reported GALAS model is proposed as a useful tool for virtual screening of compounds for possible drug-drug interactions even prior to the actual synthesis.

Publication types

  • Evaluation Study

MeSH terms

  • Artificial Intelligence*
  • Computer-Aided Design
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 CYP3A Inhibitors*
  • Databases, Factual
  • Drug Design
  • Drug Evaluation, Preclinical / methods*
  • Drug Evaluation, Preclinical / statistics & numerical data*
  • Drug Interactions
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • In Vitro Techniques
  • Models, Chemical
  • Quantitative Structure-Activity Relationship
  • Software
  • User-Computer Interface*


  • Cytochrome P-450 CYP3A Inhibitors
  • Enzyme Inhibitors
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human