4FM5
X-ray structure of des-methylflurbiprofen bound to murine COX-2
Summary for 4FM5
| Entry DOI | 10.2210/pdb4fm5/pdb |
| Related | 3NT1 3RR3 |
| Descriptor | Prostaglandin G/H synthase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, octyl beta-D-glucopyranoside, ... (6 entities in total) |
| Functional Keywords | membrane protein, cyclooxygenase, heme binding, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Mus musculus (mouse) |
| Total number of polymer chains | 4 |
| Total formula weight | 283210.36 |
| Authors | Xu, S.,Banerjee, S.,Windsor, M.A.,Marnett, L.J. (deposition date: 2012-06-15, release date: 2012-08-29, Last modification date: 2024-11-06) |
| Primary citation | Windsor, M.A.,Hermanson, D.J.,Kingsley, P.J.,Xu, S.,Crews, B.C.,Ho, W.,Keenan, C.M.,Banerjee, S.,Sharkey, K.A.,Marnett, L.J. Substrate-Selective Inhibition of Cyclooxygenase-2: Development and Evaluation of Achiral Profen Probes. ACS Med Chem Lett, 3:759-763, 2012 Cited by PubMed Abstract: Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid and the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA). We recently reported that (R)-profens selectively inhibit endocannabinoid oxygenation but not arachidonic acid oxygenation. In this work, we synthesized achiral derivatives of five profen scaffolds and evaluated them for substrate-selective inhibition using in vitro and cellular assays. The size of the substituents dictated the inhibitory strength of the analogs, with smaller substituents enabling greater potency but less selectivity. Inhibitors based on the flurbiprofen scaffold possessed the greatest potency and selectivity, with desmethylflurbiprofen (3a) exhibiting an IC(50) of 0.11 μM for inhibition of 2-AG oxygenation. The crystal structure of desmethylflurbiprofen complexed to mCOX-2 demonstrated a similar binding mode to other profens. Desmethylflurbiprofen exhibited a half-life in mice comparable to that of ibuprofen. The data presented suggest that achiral profens can act as lead molecules toward in vivo probes of substrate-selective COX-2 inhibition. PubMed: 22984634DOI: 10.1021/ml3001616 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.81 Å) |
Structure validation
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