title: Rationalizing the activities of diverse cholecystokinin 2 receptor antagonists using molecular field points.
abstract: Cholecystokinin 2 receptor antagonists encompass a wide range of structures. This makes them unsuitable candidates for existing 3D-QSAR methods and has led us to develop an alternative approach to account for their observed biological activities. A diverse set of 21 antagonists was subjected to a novel molecular field-based similarity analysis. The hypothesis is that compounds with similar field patterns will bind at the same target site regardless of their underlying structure. This initial report demonstrates a linear correlation between ligand similarity and biological activity for this challenging data set. A model generated with three molecules was used to predict the activity of 18 test compounds, with different chemotypes, with a root-mean-square error of 0.68 pKB units. The ability to automatically derive a molecular alignment without knowledge of the protein structure represents an improvement over existing pharmacophore methods and makes the method particularly suitable for scaffold-hopping.
authors.affiliation: James Black Foundation, London, UK. c.low@imperial.ac.uk
authors.forename: Caroline M R
authors.initials: CM
authors.lastname: Low
authors.forename: J G
authors.initials: JG
authors.lastname: Vinter
mesh_terms: D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology; D003510:Cyclohexanes / Q000737:chemistry / Q000494:pharmacology; D005753:Gastric Mucosa / Q000378:metabolism; D006168:Guinea Pigs; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000494:pharmacology; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D016018:Least-Squares Analysis; D008024:Ligands; D016014:Linear Models; D008958:Models, Molecular; D010179:Pancreas / Q000166:cytology; D010795:Phthalic Acids / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D043886:Receptor, Cholecystokinin A / Q000037:antagonists & inhibitors; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D001565:Benzoates; D001952:Bridged-Ring Compounds; D003510:Cyclohexanes; D006574:Heterocyclic Compounds, 2-Ring; D008024:Ligands; D010795:Phthalic Acids; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B