Exploration of binding site pattern in arachidonic acid metabolizing enzymes, Cyclooxygenases and Lipoxygenases

Abstract

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.

Synthesis, anti-inflammatory, analgesic, 5-lipoxygenase (5-LOX) inhibition activities, and molecular docking study of 7-substituted coumarin derivatives

“…A total number of 27 compounds were synthesized in good yield. The synthesized compound were characterized by FTIR, 1 H and 13 C NMR, mass spectra (ESI-MS), and elemental analysis. In vivo anti-inflammatory and analgesic activity, and in vitro LOX enzyme inhibition study revealed that compound 33 and 35…”

“…We also performed in-vitro soybean LOX inhibition assay for screening of synthesized compounds as 5-LOX inhibitors. Reddy et al [13] compared binding sites of soybean lipoxygenase with human 5-LOX, and reported that both shared almost the same similarity with each other. We also compared amino acid binding sites in human 5-LOX and soybean 3-LOX by the comparison of physicochemical properties using MultiBind program at http://bioinfo3d.cs.tau.ac.il/MultiBind/.…”

Inhibitory Activity of Andrographolide and Andrograpanin on the Rate of PGH2 Formation

“…Formation of the enzyme-inhibitor complex prevents the binding of the substrate to the enzyme, therefore blocks the catalytic conversion of the substrate, in this case is arachidonic acid, to product, which is PGH 2 . 9 The structural requirements for the timedependent inhibition of prostaglandin biosynthesis by different anti-inflammatory drugs were first evaluated by Rome and Lands, who studied ibuprofen, mefenamic acid, and flurbiprofen. A kinetic model was developed to explain their observations in which there is an initial rapid, reversible binding of the inhibitor to the enzyme characterized by a dissociation constant, K I , followed by an essentially irreversible time-dependent change in the enzyme−inhibitor complex characterized by the rate constant.…”

Probing the orientation of inhibitor and epoxy-eicosatrienoic acid binding in the active site of soluble epoxide hydrolase

“…It has also been used to identify new structural scaffold for drug design. [23-31] Molecular docking or molecular dynamics simulation have been used to identify potent inhibitors for sEH. [28, 32-34] Moreover, the catalytic mechanism of sEH on model substrates was well studied by computational models.…”