Essential structural profile of a dual functional inhibitor against cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX): Molecular docking and 3D-QSAR analyses on DHDMBF analogues Mingyue Zheng, Zhenshan Zhang, Weiliang Zhu, * Hong Liu, * Xiaomin Luo, Kaixian Chen and Hualiang Jiang * Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, PR China Received 25 November 2005; revised 29 December 2005; accepted 30 December 2005 Available online 2 February 2006 Abstract—It is recently proposed that compounds with equal capabilities of inhibiting COX and 5-LOX, both are key enzymes involved in the arachidonic acid (AA) cascade, are expected to be safer non-steroidal anti-inflammatory drugs (NSAIDs). To dig out helpful information in designing dual functional inhibitors against the two enzymes, homology modeling, molecular dynamics (MD) simulations, automated docking, and 3D-QSAR analyses were performed in this study on 21 COX-2/5-LOX dual inhibitors, namely, 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran (DHDMBF) analogues. A 3D-model of 5-LOX was built based on the high-resolution X-ray structure of rabbit reticulocyte 15-lipoxygenase. Molecular docking was then applied to locate the binding orientations and conformations of DHDMBF analogues with COX-2 and 5-LOX, respectively, leading to highly predictive CoMFA models constructed on the basis of the binding conformations with q 2 values of 0.782 and 0.634 for COX-2 and 5-LOX, respectively. In addition, CoMFA field distributions were found in good agreement with the structural characteristics of the corresponding bind- ing sites. Both the docking simulations and QSAR analyses suggest that new potent dual inhibitors should share a structural feature with a moderately bulky group at R 2 position and a rather negatively charged group around the position of the carbonyl group of DHDMBFs. Therefore, the final 3D-QSAR models and the information of the inhibitor–enzyme interaction should be useful in developing new NSAIDs as anti-inflammation drugs with favorable safety profile. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction The withdrawal of rofecoxib (Vioxx) in 2004 aroused public concerns about the safety of non-steroidal anti- inflammatory drugs (NSAIDs) that formed the main- stay in the treatment of inflammatory disease. 1 The action mechanism of the drug is to inhibit cyclooxygen- ases (COXs), which are involved in the formation of prostaglandins and thromboxanes from arachidonic acid (AA) in cellular membranes. 2,3 However, it has been pointed out that inhibiting COX pathway could shunt the metabolism of AA toward the 5-lipoxygenase (5-LOX) pathway, 4 increasing the formation of leukotri- enes, leading to inflammation and NSAIDs-induced ad- verse effects, e.g., asthma and gastrointestinal damage that is the most troublesome side effect of NSAIDs. 4–6 On the other hand, 5-LOX was found to play an etiolog- ical role in both cardiovascular and cerebrovascular dis- eases. 5–7 Products of the 5-LOX pathway, LTB 4 and LTE 4 , are detectable in atherosclerotic lesions. 8,9,6,10 Very recently, genetic studies have associated 5-LOX and its accessory protein, 5-LOX-activating protein, with cardiovascular disease, myocardial infarction, and stroke. 7,11–13 Lo ¨tzer et al. proposed a ‘‘5-LOX athero- sclerosis hypothesis’’ 14 that further stresses the 5-LOX atherosclerosis connection. Combined with the earlier studies that COX inhibition alone leads to an up-regula- tion of AA metabolism by the 5-LOX pathway, 15 it is no more difficult to find out latent cardiovascular hazards of COX-2 selective NSAID. Therefore, it is expected that Bioorganic & Medicinal Chemistry 14 (2006) 3428–3437 0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2005.12.062 Keywords: COX-2; 5-LOX; Dual inhibitor; NSAIDs; DHDMBF; Homology modeling; Docking; 3D-QSAR; CoMFA; CoMSIA. * Corresponding authors. Tel.: +86 21 50806600x1210; fax: +86 21 50807088; e-mail: hljiang@mail.shcnc.ac.cn