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

BMC Research Notes

Pallu Reddanna³  Polamarasetty Aparoy⁴  Ashish Gupta⁴  Veena Kumari Vidya Rajan²  Kakularam Kumar Reddy¹ 

[1] School of Life Sciences, University of Hyderabad, Hyderabad 500 046, India;Sastra University, Tirumalaisamudram, Thanjavur 613401, India;National Institute of Animal Biotechnology, Hyderabad 500049, India;Centre for Computational Biology and Bioinformatics, School of Life Sciences, Central University of Himachal Pradesh, Dharamshala 176215, India

关键词: Drug design;    Receptor based pharmacophore;    Specific inhibitors;    Arachidonic acid;    Lipoxygenase;    Cyclooxygenase;   

Others  :  1177893
DOI  :  10.1186/s13104-015-1101-4

 received in 2013-12-28, accepted in 2015-03-27,  发布年份 2015

【 摘 要 】

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.

Conclusion

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.

【 授权许可】

   
2015 Kumar et al.; licensee BioMed Central.

【 图 表 】

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