Journal of Computer-Aided Molecular Design

, Volume 16, Issue 7, pp 443–458 | Cite as

Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors

  • Lovisa Afzelius
  • Collen M. Masimirembwa
  • Anders Karlén
  • Tommy B. Andersson
  • Ismael Zamora
Article

Abstract

This study describes the use of alignment-independent descriptors for obtaining qualitative and quantitative predictions of the competitive inhibition of CYP2C9 on a serie of highly structurally diverse compounds. This was accomplished by calculating alignment independent descriptors in ALMOND. These GRid INdependent Descriptors (GRIND) represent the most important GRID-interactions as a function of the distance instead of the actual position of each grid-point. The experimental data was determined under uniform conditions. The inhibitor data set consists of 35 structurally diverse competitive stereospecific inhibitors of the cytochrome P450 2C9 and the non -inhibitor data set of 46 compounds. In a PLS discriminant analysis 21 inhibitors and 21 non-inhibitors (1 and 0 as activities) were analyzed using the ALMOND program obtaining a model with an r2 of 0.74 and a cross-validation value (q2) of 0.64. The model was externally validated with 39 compounds (14 inhibitors/25 non-inhibitors). 74% of the compounds were correctly predicted and an additional 13% was assigned to a borderline cluster. Thereafter, a model for quantitative predictions was generated by a PLS analysis of the GRIND descriptors using the experimental Ki-value for 21 of the competitive inhibitors (r2=0.77, q2=0.60). The model was externally validated using 12 compounds and predicted 11 out of 12 of the Ki-values within 0.5 log units. The discriminant model will be useful in screening for CYP2C9 inhibitors from large compound collections. The 3D-QSAR model will be used during lead optimization to avoid chemistry that result in inhibition of CYP2C9.

cytochrome P450 computational modeling CYP2C9 inhibitors enzyme inhibition 3D-QSAR discriminant PLS ALMOND GRIND descriptors 

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Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Lovisa Afzelius
    • 1
    • 2
  • Collen M. Masimirembwa
    • 2
  • Anders Karlén
    • 1
  • Tommy B. Andersson
    • 2
  • Ismael Zamora
  1. 1.Department of Organic Pharmaceutical Chemistry, Biomedical CenterUppsala UniversityUppsalaSweden
  2. 2.Department of Drug Metabolism and Pharmacokinetics & Bioanalytical ChemistryAstraZeneca R&D MölndalSweden

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