1. A simple method for visualizing the differences between related receptor sites.
- Author
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Sheridan RP, Holloway MK, McGaughey G, Mosley RT, and Singh SB
- Subjects
- Algorithms, Animals, Bacterial Proteins chemistry, Binding Sites, Computer Simulation, Factor Xa chemistry, HIV Protease chemistry, Humans, Ligands, Mitogen-Activated Protein Kinase 1 chemistry, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases chemistry, Models, Molecular, Molecular Conformation, Molecular Structure, Rats, Structure-Activity Relationship, Tetrahydrofolate Dehydrogenase chemistry, Thrombin metabolism, Trypsin chemistry, p38 Mitogen-Activated Protein Kinases, Protein Conformation, Receptors, Cell Surface chemistry
- 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.
- Published
- 2002