Journal of Computer-Aided Molecular Design

, Volume 18, Issue 5, pp 309–331

Three-dimensional quantitative structure-activity and structure-selectivity relationships of dihydrofolate reductase inhibitors

  • Jeffrey J. Sutherland
  • Donald F. Weaver

DOI: 10.1023/B:JCAM.0000047814.85293.da

Cite this article as:
Sutherland, J.J. & Weaver, D.F. J Comput Aided Mol Des (2004) 18: 309. doi:10.1023/B:JCAM.0000047814.85293.da


Three-dimensional quantitative structure-activity relationship (3D-QSAR) modelling using comparative molecular similarity indices analysis (CoMSIA) was applied to a series of 406 structurally diverse dihydrofolate reductase (DHFR) inhibitors from Pneumocystis carinii (pc) and rat liver (rl). X-ray crystal structures of three inhibitors bound to pcDHFR were used for defining the alignment rule. For pcDHFR, a QSAR model containing 6 components was selected using leave-10%-out cross-validation (n=240, q2=0.65), while a 4-component model was selected for rlDHFR (n=237, q2=0.63); both include steric, electrostatic and hydrophobic contributions. The models were validated using a large test set, designed to maximise its diversity and to verify the predictive accuracy of models for extrapolation. The pcDHFR model has r2=0.60 and mean absolute error (MAE) = 0.57 for the test set after removing 4 outliers, and the rlDHFR model has r2=0.60 and MAE = 0.69 after removing 4 test set outliers. In addition, classification models predicting selectivity for pcDHFR over rlDHFR were developed using soft independent modelling by class analogy (SIMCA), with a selectivity ratio of 2 (IC50,rlDHFR/ IC50,pcDHFR) used for delimiting classes. A 5-component model including steric and electrostatic contributions has cross-validated and test set classification rates of 0.67 and 0.68 for selective inhibitors, and 0.85 and 0.72 for unselective inhibitors. The predictive accuracy of models, together with the identification of important contributions in QSAR and classification models, offer the possibility of designing potent selective inhibitors and estimating their activity prior to synthesis.

3D-QSAR CoMSIA dihydrofolate reductase inhibitors Pneumocystis carinii rat liver SIMCA 

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Jeffrey J. Sutherland
    • 1
  • Donald F. Weaver
    • 2
    • 2
  1. 1.Department of ChemistryQueen's UniversityKingstonCanada
  2. 2.Departments of Medicine (Neurology) and Chemistry and School of Biomedical EngineeringDalhousie University, HalifaxNova ScotiaCanada

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