title: Classification and comparison of ligand-binding sites derived from grid-mapped knowledge-based potentials.
abstract: We describe the application of knowledge-based potentials implemented in the MOE program to compare the ligand-binding sites of several proteins. The binding probabilities for a polar and a hydrophobic probe are calculated on a grid to allow easy comparison of binding sites of superimposed related proteins. The method is fast and simple enough to simultaneously use structural information of multiple proteins of a target family. The method can be used to rapidly cluster proteins into subfamilies according to the similarity of hydrophobic and polar fields of their ligand-binding sites. Regions of the binding site which are common within a protein family can be identified and analysed for the design of family-targeted libraries or those which differ for improvement of ligand selectivity. The field-based hierarchical clustering is demonstrated for three protein families: the ligand-binding domains of nuclear receptors, the ATP-binding sites of protein kinases and the substrate binding sites of proteases. More detailed comparisons are presented for serine proteases of the chymotrypsin family, for the peroxisome proliferator-activated receptor subfamily of nuclear receptors and for progesterone and androgen receptor. The results are in good accordance with structure-based analysis and highlight important differences of the binding sites, which have been also described in the literature.
authors.affiliation: Orion Pharma, Medicinal Chemistry, P.O. Box 65, FIN-02101 Espoo, Finland.
authors.forename: Christian
authors.initials: C
authors.lastname: Hoppe
authors.forename: Christoph
authors.initials: C
authors.lastname: Steinbeck
authors.forename: Gerd
authors.initials: G
authors.lastname: Wohlfahrt
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry* / Q000145:classification; D011506:Proteins / Q000737:chemistry* / Q000145:classification; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000145:classification
chemical_list: D008024:Ligands; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011494:Protein Kinases