5BQG
Crystal Structure of mPGES-1 Bound to an Inhibitor
Summary for 5BQG
| Entry DOI | 10.2210/pdb5bqg/pdb |
| Descriptor | Prostaglandin E synthase, 2-chloro-N-(4-phenyl-1,3-thiazol-2-yl)benzamide, GLUTATHIONE, ... (8 entities in total) |
| Functional Keywords | mpges-1, enzyme, integral membrane protein, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 18742.65 |
| Authors | Fisher, M.J.,Schiffler, M.A.,Kuklish, S.L.,Antonysamy, S.,Luz, J.G. (deposition date: 2015-05-29, release date: 2016-04-13, Last modification date: 2024-03-06) |
| Primary citation | Schiffler, M.A.,Antonysamy, S.,Bhattachar, S.N.,Campanale, K.M.,Chandrasekhar, S.,Condon, B.,Desai, P.V.,Fisher, M.J.,Groshong, C.,Harvey, A.,Hickey, M.J.,Hughes, N.E.,Jones, S.A.,Kim, E.J.,Kuklish, S.L.,Luz, J.G.,Norman, B.H.,Rathmell, R.E.,Rizzo, J.R.,Seng, T.W.,Thibodeaux, S.J.,Woods, T.A.,York, J.S.,Yu, X.P. Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors. J.Med.Chem., 59:194-205, 2016 Cited by PubMed Abstract: As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 μM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8·H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate. PubMed: 26653180DOI: 10.1021/acs.jmedchem.5b01249 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.436 Å) |
Structure validation
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