title: A simple method for visualizing the differences between related receptor sites.
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.
authors.affiliation: Department of Molecular Systems, Merck Research Laboratories, Rahway, NJ 07065, USA. sheridan@merck.com
authors.forename: Robert P
authors.initials: RP
authors.lastname: Sheridan
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.forename: Georgia
authors.initials: G
authors.lastname: McGaughey
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Mosley
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry; D001426:Bacterial Proteins / Q000737:chemistry; D003198:Computer Simulation; D016333:HIV Protease / Q000737:chemistry; D006801:Humans; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry; D008958:Models, Molecular; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry*; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry; D013917:Thrombin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D001426:Bacterial Proteins; D008024:Ligands; D011956:Receptors, Cell Surface; D013762:Tetrahydrofolate Dehydrogenase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; D016282:Aspartic Acid Endopeptidases; D016333:HIV Protease