422 Letters in Drug Design & Discovery, 2007, 4, 422-425 The Molecular Basis of COX-2 Versus COX-1 Selectivity of Lumiracoxib by Molecular Docking Studies Célia M. Corrêa a,b , André F. de Paula a,c , Gilberto M.S. da Silva a , Carlos M.R. Sant’Anna a,d , Carlos A. M. Fraga a and Eliezer J. Barreiro *,a a Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, P.O. Box 68006, Rio de Janeiro, RJ, ZIP 21944-971, Brazil; b Departamento de Farmácia, Escola de Farmácia, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil; c Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; d Departamento de Química, ICE, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, Brazil Received March 05, 2007: Revised May 10, 2007: Accepted May 15, 2007 Abstract: A molecular rational basis for the COX-2/COX-1 selectivity of lumiracoxib using molecular docking approach is described. The COX-2 docking analysis for lumiracoxib and the diclofenac analogue revealed a similar binding mode, in contrast with the COX-1 docking analysis which revealed a different binding orientation for both inhibitors. Keywords: Cyclooxygenase-1, Cyclooxigenase-2, Molecular docking, NSAID´s, Lumiracoxib, Diclofenac. 1. INTRODUCTION N N CF 3 H 3 C H 2 NO 2 S NH OH Cl Cl O NH OH F Cl O H 3 C F O H 3 C O 1 2 3 4 CH 3 Cyclooxygenase-2 (COX-2) is an important therapeutic target to control the symptomatic effects of acute and chronic inflammatory response [1, 2]. COX-2 expression is selectively induced by proinflammatory cytokines IL-1 and TNFa, and promotes the biosynthesis of prostaglandins involved in the evolution of the inflammatory process. Selective inhibitors of the COX-2 isoform, like celecoxib [1], represents new generation of nonsteroidal antiinflamatory drugs (NSAIDs) with a safer gastrointestinal profile [3,4], compared with traditional COX-1 inhibitors, such as diclofenac (2). Despite has been demonstrated that diclofenac is able to inhibit both COX-1 and COX-2 isoenzymes, it showed to be more active against COX-2 than other classical NSAIDs [5,6]. Actually, pronunciated COX-2/COX-1 selectivity seems to be associated with potencial therapeutic risk [7]. In this context, an important strategy for the development of new NSAIDs is the structural modification of non-selective COX inhibitors in order to improve COX-2 selectivity. Applying this strategy, lumiracoxib (3) a diclofenac (2) bioisostere [10, 11] with selective action on COX-2 was launched [8, 9]. Considering the enormous structural similarity between diclofenac and lumiracoxib, we were prompted to evaluate in silico, by using molecular docking approach, the molecular interactions of both inhibitors with COX isoforms, in order to better understand the molecular basis involved in the COX-2 versus COX-1 selectivity, displayed by lumiracoxib. into the active site of the both enzymes to assess the efficiency of the FlexX program for docking known ligands of both COX isoforms. FlexX docked the ligands (4) in COX-1 and diclofenac in COX-2 at the same pockets as in the crystal structures, with RMS values of 1.098 Å and 0.972 Å, respectively. Based on these results, we implemented the docking study of lumiracoxib (3) and diclofenac in both COX. The results obtained for the last inhibitor, indicated that ∆ G bind of the best-fit structure in COX-2 was -22.74 kJ/mol. In accordance to the results obtained by Rowlinson et al. [12], the carboxylate group of diclofenac is hydrogen bonded to the backbone peptide bond of Ser530 and to the Tyr385 hydroxyl group. A similar binding mode was obtained for lumiracoxib, but with a less favorable ∆ G bind (-16.34 kJ/mol), which is possibly a result 2. RESULTS AND DISCUSSION We first evaluated the docking of the co-crystallized inhibitors flurbiprofen methyl ester (4) and diclofenac (2) *Address correspondence to this author at the Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, P.O. Box 68006, Rio de Janeiro, RJ, ZIP 21944-971, Brazil; E-mail: ejbarreiro@ccsdecania.ufrj.br 1570-1808/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd.