title: Insights into the structure activity relationship of mPGES-1 inhibitors: Hints for better inhibitor design.
abstract: 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.
authors.affiliation: Centre for Computational Biology and Bioinformatics, School of Life Sciences, Central University of Himachal Pradesh, Dharamshala, Himachal Pradesh 176215, India.
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, Himachal Pradesh 176215, India. Electronic address: aparoy@cuhimachal.ac.in.
authors.forename: Polamarasetty
authors.initials: P
authors.lastname: Aparoy
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism; D016718:Arachidonic Acid / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D020134:Catalytic Domain; D015232:Dinoprostone / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D062105:Molecular Docking Simulation; D044262:Prostaglandin H2 / Q000737:chemistry / Q000378:metabolism; D000071876:Prostaglandin-E Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D004791:Enzyme Inhibitors; D016718:Arachidonic Acid; D044262:Prostaglandin H2; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone
keywords: Arthritis; Inflammation; Molecular docking; Osteoarthritis; Structure-activity relationship; mPGES-1