Molecular Modelling Studies of Novel COX-2 Inhibitors

Molecular Modelling Studies of Novel COX-2 Inhibitors

A. Puratchikody, A. Umamaheswari, Navabshan Irfan, Dharmaraj Sriram
Copyright: © 2019 |Pages: 31
DOI: 10.4018/978-1-5225-7326-5.ch008
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Molecular modelling uses theoretical and computational chemistry, which offers insight into the nature of molecular systems. This chapter highlights the theoretical explanation of molecular modelling methods and describes the designing of novel tyrosine COX-2 inhibitors using molecular modelling as an example. As a first step, fragment-based drug design is used to design the novel tyrosine analogues and ligand-based drug design such as QSAR, and pharmacophore was used to identify the descriptors, ensemble of steric and electronic features, which is responsible for the selective COX-2 inhibition. The next step, structure-based drug design, was used to analyses intra- and intermolecular interactions in the drug receptor system to improve the binding affinity and pharmacokinetic properties. Finally, the pharmacokinetic and toxicity properties were predicted quantitatively using rationalization of observed structure-activity relationships and the results are reported.
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COX-2 Inhibitors

The design of new anti-inflammatory agents (COX-2 inhibitors) continues to be a tough task due to complexity of the inflammatory process. Production of prostaglandins, the inflammatory mediators depend on the enzyme cyclooxygenases (COX-1 and COX-2). Cyclooxygenases catalyse the oxygenation of biologically active C20 metabolites of arachidonic acid (AA) to produce inflammatory eicosanoids namely, prostaglandins and thromboxane. These key regulatory enzymes facilitate a range of physiological and pathophysiological functions in variety of cells within the body (Blobaum & Marnett, 2007).

The discovery of nonsteroidal anti-inflammatory drugs (NSAIDs) inhibiting prostaglandin synthesis in guinea pig lung and human platelets established COX-1 as an inflammatory target for the ancient class of drugs (Vane, 1971; Smith &Willis, 1971; Ferreria et al. 1971). The subsequent discovery of COX-2 in 1991 during inflammation, recommended that this form of the enzyme signifies the molecular target for the anti-inflammatory effects of NSAIDs (Xie et al., 1991; Fu et al. 1990; Kujubu et al. 1991; Patel et al. 2009). The primary form of COX-1 expressed in the gastrointestinal (GI) tract directed to the search for selective COX-2 inhibitors as potential anti-inflammatory drugs. The new finding of COX-2 inhibitors unveil the reduced GI side effects when compared to gastric side effects exhibited by traditional NSAIDs (Kawai et al. 2005; Al-Hourani et al. 2011; Pairet et al., 1996). As a result, some highly selective COX-2 inhibitors were introduced in the market vizcelecoxib, rofecoxib, valdecoxib, etoricoxib, and lumiracoxib (Prasit & Riendeaue, 1997; Talley, 1999; Talley et al., 1999; Chan et al., 1999; Esser et al., 2005; Marnett et al., 2009). Later on, researchers in United States and Europe conducted long-term placebo-controlled studies that revealed the existence of cardiac side effects in the above cited COX-2 inhibitors. It led to withdrawal of valdecoxib and rofecoxib from the market. These risks until now are assumed to be due to the presence of COX-2 in blood vessels. Later on, it was reported that COX-2 is in fact largely absent in major blood vessels (Ahmetaj-Shala et al., 2015; Hochstrasser, 20017; Liu et al., 2012). This critical information on role of COX-2 in chronic inflammatory disease paved the way to the researchers for rational design of selective COX-2 inhibitors with devoid of cardiovascular and GI events.

On review of literature, abundant information on structural activity relationship of different COX-2 inhibitors was studied. Sing et al. (2004) reported that substitution of methane sulfonamide at various positions of 1, 5-diaryl pyrazole influences the COX-2 inhibiting activity. In particular, introduction of 4-methanesulfonamide group at position-4 of the C-5 phenyl ring of 1, 5-diaryl pyrazoles induced the COX-2 inhibitory activity. This report is on par with the studies of Penning et al., (1997), who found that the most effective COX-2 inhibitor, nimesulide possesses methane sulfonamide group at para position of phenyl ring. Further, Zargi et al (2011) have reported a series of 1,3-diaryl urea and it possess methane sulphonyl functional group at the para position of N-1 phenyl ring and addition of diverse substituents viz -H, -F, -Cl, -Me and -OMe at the para-position of N-3 phenyl ring which enhances COX-2 selective inhibition. During the search of literature, we excavated out that the majority of the research reported so far possess similar pharmacophores with enhanced COX-2 selectivity (Chaudhary et al, 2010; Bali et al, 2012).

The authors of this chapter have taken tyrosine as their core nucleus to design a series of selective COX-2 inhibitors. In this concern, an investigation was made on tyrosine scaffold from the natural sources, since it possesses sterically more complex structure and exhibit advanced binding characteristics compared with synthetic tyrosine compounds (Lahlou, 2013). These quite distinct structural characters may enhance the non-existence of cardiovascular side effects and direct towards COX-2 selectivity. It is found that the complex structures of bioactive dibromotyrosine derivatives obtained from natural sources have proven to possess anti-inflammatory activity (Peng & Hamann, 2005). Therefore, tyrosine scaffolds derived from natural sources are of great interest as candidate COX-2 inhibitor with negligible side effects.

This novel tyrosine skeleton is a proof of principle to be further developed by substituting methane sulphonyl group at p-position of tyrosine moiety along with electron donating groups for enhancing COX-2 inhibiting activity. It is understood from the literature that substitutions of different alkyl, aryl and heteroaryl groups at –OH position of tyrosine nucleus inhibited angiogenesis, growth and development of malignant cells and their migration into the surrounding tissues with negligible toxicity on the living cells (Sallam et al, 2010). It is speculated that substitution of alkyl and aryl groups at –OH position of tyrosine nucleus may eliminate the cardiovascular problems exhibited by COX-2 inhibitors.

Herein, we report how we virtually improved the selectivity of designed tyrosine molecules towards the enzyme COX-2 in order to reduce the risk of cardiovascular events by computational molecular modelling approaches. The section 2 explains various methods adopted in our studies for designing a series of COX-2 inhibitors.

Key Terms in this Chapter

Cyclo-Oxygenase: An enzyme that catalyzes the conversion of arachidonic acid to prostaglandins and that has two isoforms of which one is involved in the creation of prostaglandins which mediate inflammation and pain.

Molecular Descriptor: The molecular descriptor is the final result of a logic and mathematical procedure which transforms chemical information encoded within a symbolic representation of a molecule into a useful number or the result of some standardized experiment.

Molecular Modelling: Molecular modelling is a technique for deriving, representing and manipulating the structures and reactions of molecules, and those properties that are dependent on these three-dimensional structures.

BBB: The blood-brain barrier is composed of high-density cells restricting passage of substances from the bloodstream much more than do the endothelial cells in capillaries elsewhere in the body.

Pharmacophore: A set of structural features in a molecule that is recognized at the receptor site and is responsible for that molecule’s biological activity.

Solubility: Amount of a substance (called the solute) that dissolves in a unit volume of a liquid substance (called the solvent) to form a saturated solution under specified conditions of temperature and pressure. Solubility is usually expressed as moles of solute per 100 grams of solvent.

Hepatotoxicity: Implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease. The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents.

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