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Due to the regulatory role of PPARs, in the expression of genes associated with various diseases such as cancer, diabetes, atherosclerosis and obesity, the pharmaceutical industry is actively investigating PPARs and their binding mechanism with different ligands. The agonists of PPAR-α, β / δ and γ are used to design drugs for high levels of cholesterol, diabetes and inflammation, respectively. However, these drugs have some side effects and limitations. Therefore, there is still a need to find the potential pharmacological targets for PPARs. After binding to ligands, PPARs act as transcription factors and control lipid and glucose metabolism (Collino et al., 2008). The search is on for the design of novel therapeutic signalling targets as the currently available therapies have proven to be highly unsatisfactory. Recent research suggests that PPARs play an important role in the pathophysiology of various disorders of the central nervous system (Collino et al., 2008).

59 The limitations of currently used PPAR-based drugs have laid a foundation for the current docking study of finding the new ligands that activate PPARs. PPAR-based anti-diabetic and hypolidemic drugs cannot be used in patients with high lipid levels (Gani et al., 2008). PPAR-γ is the molecular target for TZDs which are widely used anti-diabetic drugs. TZDs are effective in treating diabetes if they don’t cause any side effects like obesity and cardiovascular risks (Malapaka et al., 2012). PPAR-α based lipid-lowering fibrate drugs are limited in their efficacy due to restricted selectivity (Sierra et al., 2007). Therefore, there is a need to find potential agonists of PPAR- α and γ that cause little or no side effects. Moreover, the dual agonists of PPAR-α and γ are of interest to the pharmaceutical industry. Although a similar docking study was conducted previously for the binding affinities of PPARs, the study was limited to DHA (Gani et al., 2008). PPAR δ reduces the level of triglycerides and low density lipo-proteins and increases the level of high density lipo-protein cholesterol. A potential therapeutic target for PPAR δ is to be investigated (Staels et al., 2005). Previous research also suggested that PPAR-γ has a therapeutic potential to treat inflammatory diseases and certain cancers (Murphy et al., 2000).

RXR α and RAR γ regulate retinoic acid target genes. RXR α forms a heterodimeric complex with PPAR-γ and used in the treatment of breast cancer. It was observed in an in vitro study that PPAR-RXR selective ligands can be used in cancer therapy (Crowe et al., 2004). The combined therapy of PPAR and RXR ligand for breast cancer treatment is under research. An

in vitro study suggested that RXR selective ligands are capable of inhibiting the proliferation of breast cancer cells and caused regression of the disease (Crowe et al., 2004). It holds the therapeutic potential for the treatment of metabolic diseases (Pérez et al., 2012). The therapeutic role of RARs and RXRs can be modulated by ligand which binds to RAR and RXR. Although the powerful anticancer drugs are targeted by these receptors, their use is

60 limited by toxicity. This implies the need of more selective ligands that might overcome such problems (de Lera et al., 2007).

COX inhibitors play a role in reducing the risks of pancreatic cancer as they can induce apoptosis (cell death). It was observed in a research study that the risk of pancreatic cancer is 60% lower in people who use aspirin (NSAID acts as a COX inhibitor) six or more times a week (Ding et al., 2003). NSAIDs use arachidonic acid as the substrate of COX-1 and COX-2. However, NSAIDs cause some side effects like dyspepsia (stomach upset), edema (swelling of the skin due to alteration in kidney function) and gastric irritation (Krönke et al., 2009). Chronic use of COX-2 inhibitors (eg. Vioxx scandal) is linked to heart attack and stroke leading to death. Further research is needed to find selective inhibitors of COX-2 (Brown et al., 2005).

Different types of Lipoxygenases (5-LOX, 8-LOX, 12-LOX, and 15-LOX), after binding to arachidonic acid and other substrates, form several intermediate products which are involved in the development and progression of human cancers and atherosclerosis (DeWitt, 1999). Moreover, elevated levels of LOX metabolites are observed in lung, prostate, breast, colon and skin cancer cells (Kuhn, 2005). The inhibitors of LOX (eg. Zileuton- a LOX based drug used to treat asthma) can be used in the treatment of asthma, inflammation, arthritis and psoriasis (Kuhn, 2005). The use of dual inhibitors is an interesting approach as both COX and LOX derivatives are also involved in cancer proliferation apart from inflammation (Leval et al., 2002). There is a need for further research to explain the role of LOX in reducing the risk of pancreatic cancer (Ding et al., 2003). Research is being carried out actively to find the dual inhibitors of both COX and LOX.

Cannabinoid Receptors in hippocampus of the brain play an important role in learning and memory formation. The research done so far on endocannabinoid system has identified

61 Δ9-tetrahydrocannabinol (Δ9-THC), HU-210, CP55940, R-(+) -WIN55, 212-2 and anandamide as the agonists of cannabinoid receptor 1 and 2 (Davies et al., 2002). Δ9-THC is the most widely used cannabinoid drug. However, Δ9-THC causes some psychotropic side effects like sleepiness, euphoria, anxiety, confusion, nausea, dizziness (Naef et al., 2003). Hence there is still a need to find potential agonists of cannabinoid receptors, which result in few or no side effects. CB1 and CB2 receptors are attractive targets for the design of therapeutic ligands. Several endogenous ligands, for which cannabinoid receptors are the substrates, were already discovered as a result of the past research (Pavlopoulos et al., 2006).