A CoMFA study of COX-2 inhibitors with receptor based alignment Prasanna A. Datar, Evans C. Coutinho * Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai 400 098, India Received 14 May 2004; received in revised form 23 July 2004; accepted 23 July 2004 Available online 27 August 2004 Abstract A diverse set of 53 cyclooxygenase-2 (COX-2) inhibitors which were aligned in two different ways were subjected to CoMFA analysis. The first method of alignment of the molecules was based on the binding information sourced from the crystallographic study, from which CoMFA Model 1 was derived. The second mode of alignment was generated by docking the inhibitors in the binding pocket using the DOCK and AFFINITY suite of programs; this gave a second model. The CoMFA Model 2 was slightly better than Model 1 in terms of the statistical parameters r 2 and q 2 . The two models could predict very well the activity of a test set of diverse molecules, with a predictive r 2 of 0.593 and 0.768, respectively. Besides the QSAR results, the docking studies give a deep insight into the H-bonding interactions between the inhibitors and residues in the active site of the enzyme, which can be exploited in designing better inhibitors. Useful ideas on activity improvement could be gleaned from these models. # 2004 Elsevier Inc. All rights reserved. Keywords: COX-2; 3D-QSAR; CoMFA; Docking; Ligand–receptor interaction 1. Introduction Cyclooxygenase-2 (COX-2) inhibition has been one of the most widely investigated areas of research in the last decade. Pain is a common symptom in many disorders, and relief of pain has become one of the prime objectives. The discovery that the key enzyme cyclooxygenase in the ara- chidonic acid metabolism, exists in two isoforms, namely, the constitutive cyclooxygenase-1 (COX-1) and the induci- ble cyclooxygenase-2 (COX-2), has generated new avenues for drug design [1]. Both forms differ in their regulation and expression. COX-1 is responsible for the biosynthesis of prostaglandins (PGs), which are involved in the cytoprotec- tion of the gastrointestinal tract and platelet aggregation. COX-2 is induced by proinflammatory molecules such as interleukin-1 (1L-1), tumor necrosis factor-a (TNF-R), lipopolysaccharaide (LPS), and carrageenan, and plays a major role in the biosynthesis of PGs in inflammatory cells (monocytes and macrophages). The interruption of COX-1 activity may lead to gastrointestinal toxicity such as ulcera- tion, bleeding, and perforation [2]. The traditional non- steroidal anti-inflammatory drugs (NSAIDs) inhibit both COX-1 and COX-2 and hence downregulate the prostaglan- dins in almost all cells and tissues. This accounts for their anti-inflammatory activity as well as side effects. However, selective inhibition of COX-2 over COX-1 is beneficial for treatment of inflammatory diseases with reduced ulcero- genic side effects. The two COX isoforms are approximately 60% homo- logous. The ability to inhibit one isoform selectively, is attributed to the different amino acids at position 523 in the COX-1 and COX-2 enzymes [3]. The COX-1 enzyme has an isoleucine residue at this position, while the corresponding residue in the COX-2 enzyme is valine. This seemingly minute difference in structure, results in a larger central channel in the COX-2 isoform. As a result, molecules, which are too large to enter the COX-1 channel are able to enter the COX-2 channel, based solely on size discrimination at the active site. Exploitation of this phenomenon, has been the key in developing selective COX-2 inhibitors. Rational drug design has led to a wide range of diaryl- heterocycles that have been developed as selective COX-2 inhibitors. Celecoxib [4] and rofecoxib [5] were among the www.elsevier.com/locate/JMGM Journal of Molecular Graphics and Modelling 23 (2004) 239–251 * Corresponding author. Tel.: +91 22 26670871; fax: +91 22 26670816. E-mail address: evans-im@eth.net (E.C. Coutinho). 1093-3263/$ – see front matter # 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.jmgm.2004.07.003