Lipoxygenases (LOXs) are non-heme iron containing dioxygenases involved in the oxygenation of polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA). Depending on the position of insertion of oxygen, LOXs are classified into 5-, 8-, 9-, 12- and 15-LOX. Among these, 5-LOX is the most predominant isoform associated with the formation of 5-hydroperoxyeicosatetraenoic acid (5-HpETE), the precursor of non-peptido (LTB4) and peptido (LTC4, LTD4, and LTE4) leukotrienes. LTs are involved in inflammatory and allergic diseases like asthma, ulcerative colitis, rhinitis and also in cancer. Consequently 5-LOX has become target for the development of therapeutic molecules for treatment of various inflammatory disorders. Zileuton is one such inhibitor of 5-LOX approved for the treatment of asthma.In the recent times, computer aided drug design (CADD) strategies have been applied successfully in drug development processes. A comprehensive review on structure based drug design strategies in the development of novel 5-LOX inhibitors is presented in this article. Since the crystal structure of 5-LOX has been recently solved, efforts to develop 5-LOX inhibitors have mostly relied on ligand based rational approaches. The present review provides a comprehensive survey on these strategies in the development of 5-LOX inhibitors.
BackgroundCyclooxygenase (COXs) and Lipoxygenase (LOXs) pathways are the two major enzymatic pathways in arachidonic acid (AA) metabolism. The term eicosanoid is used to describe biologically active lipid mediators including prostaglandins, thromboxanes, leukotrienes and other oxygenated derivatives, which are produced primarily from AA. Eicosanoids generated in a tissue specific manner play a key role in inflammation and cancer. As AA is the substrate common to variety of COXs and LOXs, inhibition of one pathway results in diversion of the substrate to other pathways, which often is responsible for undesirable side effects. Hence there is need for development of not only isozyme specific inhibitors but also dual/multi enzyme inhibitors. Understanding the interactions of AA and characterizing its binding sites in these enzymes therefore is crucial for developing enzyme specific and multi enzyme inhibitors for enhancing therapeutic efficacy and/or overcoming side effects.ResultsAA binding sites in COXs and LOXs are identified and compared by the development of receptor based pharmacophore using MultiBind. Physico chemical properties were compared to understand the details of the binding sites in all the enzymes and to elucidate important amino acids that can be targeted for drug design. The alignment of AA binding sites in the seven enzymes COX-1, COX-2, 5-LOX, 12-LOX, 15-LOX and plant soybean LOX-1 and LOX-3 indicated a common pattern of five common interacting groups. In the same way, comparison of AA binding sites was done pair wise and by multiple alignment in various combinations. It has been identified that aliphatic and aromatic interactions are the most common in all the enzymes. In addition interactions unique to each one of these enzymes were identified.ConclusionThe complete analysis of AA binding sites in the seven enzymes was performed; 120 combinations for the seven enzymes were studied in detail. All the seven enzymes are structurally quite different, yet they share AA as the common binding partner. Comparisons in various combinations showed how they are similar and dissimilar with each other. This information will be helpful in designing specific as well as common inhibitors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13104-015-1101-4) contains supplementary material, which is available to authorized users.
Bioassay-guided fraction of the methanol extract of the roots of Pueraria tuberose DC yielded puerarin, an isoflavone C-glycoside (PT-1), isoorientin, a flavone C-glycoside (PT-2) and mangiferin, a xanthone C-glycoside (PT-3). The extracts and the isolated compounds were screened for potent antiinflammatory components inhibiting the cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX), the target enzymes of inflammation, by employing spectroscopic/polorographic methods. Among these, isoorientin was found to be a potent inhibitorof COX-2with an IC 50 value of 39 µM. Docking studies were carried out to understand the interactions of isorientin (PT-2) with COX-2.The structures of the isolates were determined by mass spectrometry and 2D-NMR techniques including HSQC, HMBC, NOESY and 1 H-1 H COSY experiments. Although isoorientin and mangiferin have been reported from several plant sources, this is the first report of their isolation from a Pueraria species.
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