title: Exploration of binding site pattern in arachidonic acid metabolizing enzymes, Cyclooxygenases and Lipoxygenases.
abstract: BACKGROUND
  Cyclooxygenase (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.
  
  
  RESULTS
  AA 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: School of Life Sciences, University of Hyderabad, Hyderabad, 500 046, India. kumar.1416@gmail.com.
authors.forename: Kakularam Kumar
authors.initials: KK
authors.lastname: Reddy
authors.affiliation: Sastra University, Tirumalaisamudram, Thanjavur, 613401, India. vidyarajan.v@gmail.com.
authors.forename: Veena Kumari
authors.initials: VK
authors.lastname: Vidya Rajan
authors.affiliation: Centre for Computational Biology and Bioinformatics, School of Life Sciences, Central University of Himachal Pradesh, Dharamshala, 176215, India. guptaashish935@gmail.com.
authors.forename: Ashish
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Centre for Computational Biology and Bioinformatics, School of Life Sciences, Central University of Himachal Pradesh, Dharamshala, 176215, India. aparoy@cuhimachal.ac.in.
authors.forename: Polamarasetty
authors.initials: P
authors.lastname: Aparoy
authors.affiliation: School of Life Sciences, University of Hyderabad, Hyderabad, 500 046, India. prsl@uohyd.ernet.in.|National Institute of Animal Biotechnology, Hyderabad, 500049, India. prsl@uohyd.ernet.in.
authors.forename: Pallu
authors.initials: P
authors.lastname: Reddanna
mesh_terms: D000595:Amino Acid Sequence; D001092:Arachidonate 12-Lipoxygenase / Q000737:chemistry*; D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry*; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry*; D016718:Arachidonic Acid / Q000737:chemistry*; D001665:Binding Sites; D017124:Conserved Sequence; D051545:Cyclooxygenase 1 / Q000737:chemistry*; D051546:Cyclooxygenase 2 / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008084:Lipoxygenase / Q000737:chemistry*; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051127:Scavenger Receptors, Class E / Q000737:chemistry*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; D016718:Arachidonic Acid; C095864:lipoxygenase 3; D008084:Lipoxygenase; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; C583212:ALOX5 protein, human