A simple method for visualizing the differences between related receptor sites.
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.
Sheridan
Robert P
RP
Department of Molecular Systems, RY50SW-100 Merck Research Laboratories, Rahway, NJ 07065, USA. sheridan@merck.com
Holloway
M Katharine
MK
McGaughey
Georgia
G
Mosley
Ralph T
RT
Singh
Suresh B
SB
D000465:Algorithms; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry; D001665:Binding Sites; D003198:Computer Simulation; D015951:Factor Xa / Q000737:chemistry; D016333:HIV Protease / Q000737:chemistry; D006801:Humans; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011487:Protein Conformation; D051381:Rats; D011956:Receptors, Cell Surface / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry; D013917:Thrombin / Q000378:metabolism; D014357:Trypsin / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases
D001426:Bacterial Proteins; D008024:Ligands; D011956:Receptors, Cell Surface; D013762:Tetrahydrofolate Dehydrogenase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014357:Trypsin; D013917:Thrombin; D015951:Factor Xa; D016333:HIV Protease