9OJS
Crystal structure of TNF alpha in complex with compound 4
This is a non-PDB format compatible entry.
Summary for 9OJS
| Entry DOI | 10.2210/pdb9ojs/pdb |
| Related | 9OJO |
| Descriptor | Tumor necrosis factor, (6R,13R,14R)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7H-6,14-methanopyrido[3',2':4,5]imidazo[1,2-b][2,5]benzodiazocin-5(14H)-one (3 entities in total) |
| Functional Keywords | tumor necrosis factor alpha, structure-based drug design, cytokine |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 3 |
| Total formula weight | 52936.00 |
| Authors | |
| Primary citation | Bian, Z.,Schmidt, R.G.,Wilson, N.S.,Duignan, D.B.,Breinlinger, E.,Dombrowski, A.W.,Erdman, P.,Foley, C.M.,Friedman, M.,Gfesser, G.A.,Goess, C.A.,Gomtsyan, A.,Judge, R.A.,Kikuchi, R.,Koshman, Y.,Liu, X.,Longenecker, K.L.,McClure, A.,Sippy, K.,Wetter, J.M.,Stoffel, R.,Vasudevan, A. Discovery of Orally Efficacious Bridged Piperazines as smTNF Modulators. J.Med.Chem., 2025 Cited by PubMed Abstract: Tumor necrosis factor α (TNFα) plays a critical role in inflammatory and autoimmune diseases. While biologic drugs have improved patient outcomes in conditions like rheumatoid arthritis by disrupting TNFα signaling, small molecule targeting has been challenging due to the strong TNF-receptor binding and difficulty in disrupting the TNF trimer. This research presents small molecule TNFα inhibitors with a novel bridged-piperazine core, developed through molecular dynamics simulation and scaffold hopping. The initial hit was optimized using structure-based design, leading to the discovery of a lead molecule with similar potency to the prototype but enhanced physicochemical properties. This lead demonstrated oral efficacy in a mouse glucose-6-phosphate isomerase-induced paw swelling model, comparable to the effects of a TNFα antibody. The estimated effective human dose is 200 mg once daily, highlighting the potential for clinical development of these compounds. PubMed: 40632677DOI: 10.1021/acs.jmedchem.5c00323 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.849 Å) |
Structure validation
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