Structure-based pharmacophore of COX-2 selective inhibitors and identification of original lead compounds from 3D database searching method

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.

Graphical abstractA structure-based four-point pharmacophore of COX-2 selective inhibitors was used to screen the Maybridge database and allowed to identify two original molecules with a new scaffold.Figure optionsDownload full-size imageDownload as PowerPoint slide