Docking studies on NSAID/COX-2 isozyme complexes using Contact Statistics analysis Giuseppe Ermondi a, *, Giulia Caron a , Raelene Lawrence b & Dario Longo c a Dipartimento di Scienza e Tecnologia del Farmaco, V.P. Giuria 9, I-10125 Torino, Italy; b Chemical Computing Group, Inc., 1010 Sherbrooke Street West, Suite 910, Montreal, Quebec, Canada H3A 2R7; c Bioindustry Park del Canavese, V. Ribes 5, I-10010 Colleretto Giacosa (TO), Italy Received 11 August 2004; accepted in revised form 14 November 2004 Ó Springer 2005 Key words: celecoxib, Contact Statistics analysis, COX-2, docking, flurbiprofen, MOE, nimesulide, NSAIDs, rofecoxib Summary The selective inhibition of COX-2 isozymes should lead to a new generation of NSAIDs with significantly reduced side effects; e.g. celecoxib (Celebrex Ò ) and rofecoxib (Vioxx Ò ). To obtain inhibitors with higher selectivity it has become essential to gain additional insight into the details of the interactions between COX isozymes and NSAIDs. Although X-ray structures of COX-2 complexed with a small number of ligands are available, experimental data are missing for two well-known selective COX-2 inhibitors (rofecoxib and nimesulide) and docking results reported are controversial. We use a combination of a traditional docking procedure with a new computational tool (Contact Statistics analysis) that identifies the best orientation among a number of solutions to shed some light on this topic. Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs) [1, 2] are of great importance in the treatment of inflammatory diseases. In 1971 [3], it was discov- ered that COXs are the molecular targets for NSAIDs; thus, inhibition of COXs leads to a decreased production of prostaglandins and tromboxanes, which, in turn, accounts for the beneficial effects of NSAIDs (e.g. anti-inflamma- tory, antipyretic, analgesic and cardiovascular effects), as well as their undesirable side effects (e.g. gastrointestinal). In the early 1990s, COX was demonstrated to exist as two distinct isoforms. COX-1 is constitu- tively expressed as a housekeeping enzyme in nearly all tissues, and mediates physiological response (e.g., cytoprotection of the stomach, platelet aggregation). COX-2, which is expressed by cells that are involved in inflammation (e.g., macrophages, monocytes, synoviocytes), has emerged as the isoform that is primarily respon- sible for the synthesis of the prostanoids involved in pathological processes, such as acute and chronic inflammatory states [4]. Classical NSAIDs (i.e., aspirin, ibuprofen, naproxen, but not nimesulide) are non-selective inhibitors of both isozymes (IC 50 for COX-1 is similar to the IC 50 for COX-2) and can cause gastric and renal failure [1, 5, 6]. Hence, there have been sustained efforts to identify selective COX-2 inhibitors (compounds whose IC 50 for COX-1 inhibitory activity is significantly above that of COX-2). Recently, the COX-2 selective inhibitors celecoxib (Celebrex Ò ) and rofecoxib (Vioxx Ò ) have been approved by the Federal *To whom correspondence should be addressed. Phone: +39- 011-6707282; Fax: +39-011-6707687; E-mail: giuseppe.ermondi@ unito.it Journal of Computer-Aided Molecular Design 18: 683–696, 2004. DOI 10.1007/s10822-004-6258-1 683