Gupta Ashish, Aparoy Polamarasetty
Centre for Computational Biology and Bioinformatics, School of Life Sciences, Central University of Himachal Pradesh, Dharamshala, Himachal Pradesh 176215, India.
Centre for Computational Biology and Bioinformatics, School of Life Sciences, Central University of Himachal Pradesh, Dharamshala, Himachal Pradesh 176215, India.
Int J Biol Macromol. 2016 Jul;88:624-32. doi: 10.1016/j.ijbiomac.2016.03.038. Epub 2016 Mar 21.
Microsomal prostaglandin E synthase-1 (mPGES-1) is a membrane protein which plays crucial role in arachidonic acid metabolism, in the catalysis of PGH2 to PGE2. It is a potential drug target involved in variety of human cancers and inflammatory disorders. In the present study we made an attempt to identify crucial amino acid residues involved in the effective binding of its inhibitors at the active site. Molecular docking and Structure Activity Relationship (SAR) studies were performed. In the present study 127 inhibitors having significant variability in parent scaffold were considered. The results clearly indicated that in the GSH and PGH2 binding site Arg70, Arg73, Asn74, Glu77, His113, Tyr117, Arg126, Ser127, Tyr130, Thr131 and Ala138 consistently form crucial interactions with inhibitors of different classes/scaffolds. These findings are consistent with that of existing reports on the active site residues pivotal at mPGES-1 active site. Further analysis suggested that out of all important amino acid residues identified; Arg73, Asn74, His113, Tyr117, Arg126, Ser127, Tyr130, Thr131 and Ala138 play a crucial role in hydrogen and π-π interactions. The identified amino acid residues can act as target sites for the design and development of drug candidates against mPGES-1.
微粒体前列腺素E合酶-1（mPGES-1）是一种膜蛋白，在花生四烯酸代谢中，即催化PGH2转化为PGE2的过程中发挥关键作用。它是一个潜在的药物靶点，涉及多种人类癌症和炎症性疾病。在本研究中，我们试图确定在其活性位点有效结合抑制剂所涉及的关键氨基酸残基。进行了分子对接和构效关系（SAR）研究。在本研究中，考虑了127种在母核支架上具有显著变异性的抑制剂。结果清楚地表明，在谷胱甘肽（GSH）和PGH2结合位点，精氨酸70、精氨酸73、天冬酰胺74、谷氨酸77、组氨酸113、酪氨酸117、精氨酸126、丝氨酸127、酪氨酸130、苏氨酸131和丙氨酸138始终与不同类别/支架的抑制剂形成关键相互作用。这些发现与关于mPGES-1活性位点关键活性位点残基的现有报道一致。进一步分析表明，在所有鉴定出的重要氨基酸残基中，精氨酸73、天冬酰胺74、组氨酸113、酪氨酸117、精氨酸126、丝氨酸127、酪氨酸130、苏氨酸131和丙氨酸138在氢键和π-π相互作用中起关键作用。所鉴定的氨基酸残基可作为针对mPGES-1的候选药物设计和开发的靶点。
