Computer Aided Drug Design Approaches to Develop Cyclooxygenase Based Novel Anti-Inflammatory and Anti-Cancer Drugs

Abstract

Cyclooxygenases (COXs), the enzymes involved in the formation of prostaglandins from polyunsaturated fatty acids such as arachidonic acid, exist in two forms--the constitutive COX-1 that is cytoprotective and responsible for the production of prostaglandins and COX-2 which is induced by cytokines, mitogens and endotoxins in inflammatory cells and responsible for the increased levels of prostaglandins during inflammation. As a result COX-2 has become the natural target for the development of anti-inflammatory and anti-cancer drugs. While the conventional NSAIDs with gastric side effects inhibit both COX-1 and COX-2, the newly developed drugs for inflammation with no gastric side effects selectively block the COX-2 enzyme. NSAIDs, nonselective non-aspirin NSAIDs and COX-2 selective inhibitors, are being widely used for various arthritis and pain syndromes. Selective inhibitors of COX-2, however, convey a small but definite risk of myocardial infarction and stroke; the extent of which varies depending on the COX-2 specificity. In view of the gastric side effects of conventional NSAIDs and the recent market withdrawal of rofecoxib and valdecoxib due to their adverse cardiovascular side effects there is need to develop alternative anti-inflammatory agents with reduced gastric and cardiovascular problems. The present study reviews various Computer Aided Drug Design (CADD) approaches to develop Cyclooxygenase based anti-inflammatory and anti-cancer drugs.

Computational analysis of R and S isoforms of 12-Lipoxygenases: Homology modeling and docking studies

“…A four-stage protocol was established for energy minimization of the solvated protein [34]. These minimizations were carried out using periodic boundary conditions in all directions and each stage involved 100 steps of steepest descent and 1500 steps of conjugate gradient optimization.…”

Homology modeling of 5-lipoxygenase and hints for better inhibitor design

“…The purine nucleoside phosphorylase (PNP) inhibitors [42,43] were designed successfully using these methods. Minimization methods were also used successfully, for predicting relative binding affinities of protease inhibitors [44], COX-2 inhibitors [45] and fructose 1-6, bisphosphatase inhibitors [46,47] using energies obtained both in solvent as well as complex phases of each inhibitor.…”

Use of Bioinformatics Tools in Different Spheres of Life Sciences

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