544 Letters in Organic Chemistry, 2008, 5, 544-554 1570-1786/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. QSAR and Docking Studies on Propenone Derivatives as Dual COX and 5- LOX Inhibitors Ponnurengam M. Sivakumar, Sethu K. Geetha Babu, Vaibhav Sharma and Mukesh Doble* Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600036, India Received January 25, 2008: Revised May 23, 2008: Accepted June 03, 2008 Abstract: Quantitative structure activity relationships were developed for seventeen propenone derivatives reported in the literature that act as dual COX and 5-LOX inhibitors. Predominantly spatial, thermodynamic, topological, and electronic descriptors appear in the models. Docking between these compounds and COX-1, COX-2 and 5-LOX enzymes was also performed and mathematical relationships were developed between the binding energy and activity. Keywords: Propenone, NSAID, QSAR, COX -1, COX-2 and 5-LOX. INTRODUCTION Inflammation is a defense and complex biological re- sponse arising due to the tissue damage or injury. Diseases like rheumatoid arthritis, multiple sclerosis, bowel inflamma- tion etc also proceed through the inflammatory pathway. Anti-inflammatory agents are classified on the basis of their target enzymes, and the latter include G-protein coupled re- ceptors, nuclear hormone receptors, cytokines and cytokine receptors and cell adhesion molecules. In the first group there are several enzyme targets, such as COX, 5-LOX and others [1]. There are three isoforms of cyclooxygenase (COX) enzymes, which include constitutive COX -1, induc- ible COX -2 [2], and variant canine COX-3 [3]. Cyclooxy- genase and lipoxygenase (LOX) play major role in the pro- duction of important biological mediators such as prosta- glandins (namely PGE 2 , PGF 2 , PGI 2 through the cyclooxy- genase pathway) and leukotrienes (LTA 4 , LTB 4 , LTC 4 , LTD 4 , LTE 4 , and LTF 4 through the lipooxygenase pathway) by acting on arachidonic acid (AA), a 20-carbon acid, which is liberated from phospholipids by the action of phospholi- pase due to external stimuli [4]. The formation of prosta- glandin further leads to inflammation and it can be prevented by inhibiting the inducible isoform of COX enzyme (specifi- cally COX-2) [5]. 5-LOX pathway generates leukotrienes, which are mediators of inflammation, asthma and allergic reactions. The actions of COX-1 are generally beneficial and constitutively expressed in most of the mammalian tissues. COX-2 is harmful as it is also involved in the biosynthesis of prostaglandin, which triggers activated macrophages and cells at the inflammation site. NSAIDs and coxibs are the two famous group of agents used for the treatment of inflammation and they act through the inhibition of COX-2 enzyme. In the 5-LOX pathway, AA is first converted to HPETE (hydroperoxy eicosatetraenoic acid), which is further converted to the unstable LTA 4 . By the action of glutathione- S-transferase, LTA 4 is converted in to cysteinyl leukotrienes (LTC 4 , LTD 4 and LTE 4 ) [6].Design of newer drugs which can act as dual COX-2 and 5-LOX inhibitor, holds promise towards the treatment of inflamma- *Address correspondence to this author at the Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600036, India; Fax: +91- 44 –22574102; E-mail: mukeshd@iitm.ac.in tion. This attempt has been made by several researchers [7- 9]. Earlier studies have reported the use of propenone com- pounds such as 1-furan-2-yl-3-pyridin-2-yl-propenone (FPP- 3) for inflammatory disorders [10], and 1, 2-disubstituted propanones as antifungal agents [11]. The wide range of bio- logical activities of 1,3-diphenyl-2-propen-1-one derivatives has been studied by other researchers [12]. Synthesis, bio- logical evaluation and structure activity relationship studies of 1, 3-diphenylprop-2-yn-1-ones as dual inhibitors of COX and LOX have also been studied by Rao et al. [13, 14]. Synthesis and QSAR studies on chalcones and their de- rivatives [15-17] bring out the structural requirements of these compounds to act as anti-tuberculosis as well as anti- bacterial agents. In the light of this collective evidence, it is concluded that propenone derivatives have dual COX and 5- LOX inhibitory activity [18]. In this paper, structure based approach such as quantitative structure activity studies, as well as target based approach, such as ligand target binding studies, were carried out on compounds whose in vitro dual enzyme inhibitory activities have been reported. The struc- ture based approach identifies the key structural features required for the molecule to exhibit high activity, whereas, the latter approach identifies the position and orientation of the ligand with respect to the amino acids present in the ac- tive site of the protein receptor or enzyme. Binding studies describe the key recognition sites and the changes that need to be done to the ligand to achieve best interaction between the two. These approaches play an important role in screen- ing large database of drugs and suggesting newer structures. MATERIALS AND METHODS Molecular modeling and quantitative structure activity re- lationships (QSAR) were developed using Cerius 2 software (Acceryls, USA) and regression analysis, and ANOVA were carried out with Kyplot ® (Kyens Lab Inc., Japan) software. The structure and the inhibitory activity data were collected from the literature [18] and are listed in Table 1. These val- ues are expressed as pIC 50 , which is equal to -log ( M). The molecular structure of propenone derivatives was built and the energy was minimized using Consistent Valence Force Field (CVFF), to arrive at the thermodynamically stable structure. This force field is also known as universal force field and it is well suited for modeling small organic mole-