title: Structure-based pharmacophore of COX-2 selective inhibitors and identification of original lead compounds from 3D database searching method.
abstract: A four-point pharmacophore of COX-2 selective inhibitors was derived from a training set of 16 compounds, using the Catalyst program. It consists of a H bond acceptor, two hydrophobic groups and an aromatic ring, in accordance with SAR data of the compounds and with topology of the COX-2 active site. This hypothesis, combined with exclusion volume spheres representing important residues of the COX-2 binding site, was used to virtually screen the Maybridge database. Eight compounds were selected for an in vitro enzymatic assay. Five of them show COX-2 inhibition close to that of nimesulide and rofecoxib, two reference COX-2 selective inhibitors. As a result, structure-based pharmacophore generation was able to identify original lead compounds, inhibiting the COX-2 isoform.
authors.affiliation: Département de Chimie, Laboratoire de Chimie Biologique Structurale, Facultés Universitaires Notre-Dame de la Paix, 61 Rue de Bruxelles, B-5000 Namur, Belgium. catherine.michaux@fundp.ac.be
authors.forename: Catherine
authors.initials: C
authors.lastname: Michaux
authors.forename: Xavier
authors.initials: X
authors.lastname: de Leval
authors.forename: Fabien
authors.initials: F
authors.lastname: Julémont
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
authors.forename: François
authors.initials: F
authors.lastname: Durant
mesh_terms: D001665:Binding Sites; D051546:Cyclooxygenase 2 / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry*; D003628:Database Management Systems; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D016861:Cyclooxygenase Inhibitors; D051546:Cyclooxygenase 2