title: A pharmacophore model for NK2 antagonist comprising compounds from several structurally diverse classes.
abstract: A neurokinin 2 (NK2) antagonist pharmacophore model has been developed on the basis of five non-peptide antagonists from several structurally diverse classes. To evaluate the pharmacophore model, another 20 antagonists were fitted to the model. By use of exhaustive conformational analysis (MMFFs force field and the GB/SA hydration model) and least-squares molecular superimposition studies, 23 of the 25 antagonists were fitted to the model in a low energy conformation with a low RMS value. The pharmacophore model is described by four pharmacophore elements: Three hydrophobic groups and a hydrogen bond donor represented as a vector. The hydrophobic groups are generally aromatic rings, but this is not a requirement. The antagonists bind in an extended conformation with two aromatic rings in a parallel displaced and tilted conformation. The model was able to explain the enantioselectivity of SR48968 and GR159897.
authors.affiliation: Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.forename: Tommy
authors.initials: T
authors.lastname: Liljefors
authors.forename: Klaus
authors.initials: K
authors.lastname: Gundertofte
authors.forename: Berith
authors.initials: B
authors.lastname: Bjørnholm
mesh_terms: D003198:Computer Simulation; D017076:Computer-Aided Design; D015195:Drug Design; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D008968:Molecular Conformation; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D018041:Receptors, Neurokinin-2