2D QSAR and similarity studies on cruzain inhibitors aimed at improving selectivity over cathepsin L

Bioorg Med Chem. 2008 Jan 15;16(2):838-53. doi: 10.1016/j.bmc.2007.10.048. Epub 2007 Oct 22.

Abstract

Hologram quantitative structure-activity relationships (HQSAR) were applied to a data set of 41 cruzain inhibitors. The best HQSAR model (Q(2)=0.77; R(2)=0.90) employing Surflex-Sim, as training and test sets generator, was obtained using atoms, bonds, and connections as fragment distinctions and 4-7 as fragment size. This model was then used to predict the potencies of 12 test set compounds, giving satisfactory predictive R(2) value of 0.88. The contribution maps obtained from the best HQSAR model are in agreement with the biological activities of the study compounds. The Trypanosoma cruzi cruzain shares high similarity with the mammalian homolog cathepsin L. The selectivity toward cruzain was checked by a database of 123 compounds, which corresponds to the 41 cruzain inhibitors used in the HQSAR model development plus 82 cathepsin L inhibitors. We screened these compounds by ROCS (Rapid Overlay of Chemical Structures), a Gaussian-shape volume overlap filter that can rapidly identify shapes that match the query molecule. Remarkably, ROCS was able to rank the first 37 hits as being only cruzain inhibitors. In addition, the area under the curve (AUC) obtained with ROCS was 0.96, indicating that the method was very efficient to distinguishing between cruzain and cathepsin L inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cathepsin L
  • Cathepsins / chemistry*
  • Cathepsins / pharmacokinetics*
  • Cathepsins / pharmacology
  • Cysteine Endopeptidases / chemistry*
  • Cysteine Endopeptidases / metabolism
  • Cysteine Endopeptidases / pharmacokinetics*
  • Cysteine Endopeptidases / pharmacology
  • Cysteine Proteinase Inhibitors / chemistry*
  • Cysteine Proteinase Inhibitors / pharmacokinetics*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / metabolism
  • Quantitative Structure-Activity Relationship
  • Trypanosoma cruzi / enzymology

Substances

  • Cysteine Proteinase Inhibitors
  • Protozoan Proteins
  • Cathepsins
  • Cysteine Endopeptidases
  • cruzain, Trypanosoma cruzi
  • Cathepsin L