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

• Published in: European journal of medicinal chemistry Vol. 41; no. 12; pp. 1446 - 1455
• Main Authors: Michaux, Catherine, de Leval, Xavier, Julémont, Fabien, Dogné, Jean-Michel, Pirotte, Bernard, Durant, François
• Format: Journal Article Web Resource
• Language: English
• Published: Oxford Elsevier Masson SAS 01-12-2006; Elsevier
• Subjects: Binding Sites; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Catalyst/HIPHOP; COX-2 selective inhibitor; Cyclooxygenase 2 - drug effects; Cyclooxygenase Inhibitors - chemistry; Database Management Systems; Hit identification; Human health sciences; Humans; Medical sciences; Models, Molecular; Molecular Structure; Pharmacie, pharmacologie & toxicologie; Pharmacology. Drug treatments; Pharmacy, pharmacology & toxicology; Sciences de la santé humaine; Structure-based pharmacophore; Virtual screening; COX-2 selective inhibitor; Virtual screening; Catalyst/HIPHOP; Structure-based pharmacophore; Hit identification; Phenanthrene derivatives; Rofecoxib; Enzyme; Coumarine derivatives; Cyclooxygenase 2; Enzyme inhibitor; Lactone; Cyclooxygenase 2 inhibitor; Selectivity; In vitro; Modeling; Non steroidal antiinflammatory agent; Structure activity relation; Molecular model; Database; Oxidoreductases; Nimesulide
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2006.07.017

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.
▪A 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.