Ligand-receptor 3-D similarity studies using multiple 4-point pharmacophores.
A new method for 3-D similarity is presented based on the multiple potential 4-point 3-D pharmacophores expressed by ligands and complementary to receptors. These are calculated for ligands taking conformational flexibility into account, and for receptors through the use of complementary site-points. Through this common frame of reference both ligand-ligand and ligand-receptor similarity studies are possible. The application of the method to selectivity between different serine proteases (thrombin, factor Xa and trypsin) is discussed, and the need to use 4-point pharmacophores rather than 3-point pharmacophores is illustrated. A novel refinement to the potential pharmacophore method that uses a "special" feature to give a relative measure of similarity/diversity is also discussed.
Mason
J S
JS
Department of Macromolecular Structure, Bristol-Myers Squibb, Princeton, NJ 08543, USA. jonathan_mason@ccmail.bms.com
Cheney
D L
DL
D003196:Computer Graphics; D015195:Drug Design; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D011955:Receptors, Drug / Q000737:chemistry* / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry; D012984:Software; D013917:Thrombin / Q000737:chemistry / Q000378:metabolism; D014357:Trypsin / Q000737:chemistry / Q000378:metabolism
D008024:Ligands; D011955:Receptors, Drug; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D014357:Trypsin; D013917:Thrombin; D015951:Factor Xa