Modeling K(m) values using electrotopological state: substrates for cytochrome P450 3A4-mediated metabolism

Bioorg Med Chem Lett. 2005 Sep 15;15(18):4076-84. doi: 10.1016/j.bmcl.2005.06.015.

Abstract

In order to determine K(m) values of substrates for CYP3A4-mediated metabolism, an in silico model has been developed in the present work. Using electrotopological state (E-state) indices, together with Bayesian-regularized neural network (BRNN), we have described an in silico method to model log(1/K(m)) values of various substrates. The relative importance of the E-state indices is analyzed by principal component analysis. By using an additional external test set, which is independent of the training set, the robustness and predictivity of the model are also validated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computational Biology
  • Cyclohexanols / chemistry
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / chemistry*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Molecular Structure
  • Principal Component Analysis
  • Pyrrolizidine Alkaloids / chemistry
  • Quantitative Structure-Activity Relationship*
  • Reproducibility of Results
  • Substrate Specificity
  • Venlafaxine Hydrochloride

Substances

  • Cyclohexanols
  • Pyrrolizidine Alkaloids
  • Venlafaxine Hydrochloride
  • Cytochrome P-450 Enzyme System
  • senecionine
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human