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A simple method for visualizing the differences between related receptor sites.

Robert P Sheridan·M Katharine Holloway·Georgia McGaughey·Ralph T Mosley·Suresh B Singh
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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.

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AnimalsAspartic Acid EndopeptidasesBacterial ProteinsComputer SimulationHIV ProteaseHumansLigandsMitogen-Activated Protein KinasesModels, MolecularProtein ConformationReceptors, Cell SurfaceTetrahydrofolate DehydrogenaseThrombinp38 Mitogen-Activated Protein KinasesJournal Article

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Robert P Sheridan, M Katharine Holloway, Georgia McGaughey, Ralph T Mosley, Suresh B Singh. 2002. A simple method for visualizing the differences between related receptor sites.. https://doi.org/10.1016/s1093-3263(02)00122-5

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