A simple method for visualizing the differences between related receptor sites

J Mol Graph Model. 2002 Aug;21(1):71-9. doi: 10.1016/s1093-3263(02)00122-5.

Abstract

Pastor and Cruciani [J. Med. Chem. 38 (1995) 4637] and Kastenholz et al. [J. Med. Chem. 43 (2000) 3033] pioneered methods for comparing related receptors, with the ultimate goal of designing selective ligands. Such methods start with a reasonable superposition of high-resolution three-dimensional (3D) structures of the receptors. Next, molecular field maps are calculated for each receptor. Then the maps are analyzed to determine which map features are correlated with a particular subset of receptors. We present a method FLOGTV, based on the trend vector paradigm [J. Chem. Inf. Comput. Sci. 25 (1985) 64] to perform the analysis. This is mathematically simpler than the GRID/CPCA method of Kastenholz et al. and allows for the simultaneous comparison of many receptor structures. Also, the trend vector paradigm provides a method of selecting isopotential contours that are well above "noise". We demonstrate the method on four examples: HIV proteases versus two-domain acid proteases, thrombin versus trypsin and factor Xa, bacterial dihydrofolate reductases (DHFRs) versus vertebrate DHFRs, and P38 versus ERK protein kinases.

MeSH terms

  • Animals
  • Aspartic Acid Endopeptidases / chemistry
  • Bacterial Proteins / chemistry
  • Computer Simulation*
  • HIV Protease / chemistry
  • Humans
  • Ligands
  • Mitogen-Activated Protein Kinases / chemistry
  • Models, Molecular
  • Protein Conformation*
  • Receptors, Cell Surface / chemistry*
  • Tetrahydrofolate Dehydrogenase / chemistry
  • Thrombin / metabolism
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Bacterial Proteins
  • Ligands
  • Receptors, Cell Surface
  • Tetrahydrofolate Dehydrogenase
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Thrombin
  • Aspartic Acid Endopeptidases
  • HIV Protease