7jra

HUMAN TNF-ALPHA IN COMPLEX WITH 2-[5-(3-chloro-4-{[(1R)-1-(2-fluorophenyl)ethyl]amino}quinolin-6-yl)pyrimidin-2-yl]propan-2-ol

spinqualitylabelsall models 7jra, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.1Å Ligands: GOL, VGY Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFalpha). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFalpha trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed. Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFalpha Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches.,Xiao HY, Li N, Duan JJ, Jiang B, Lu Z, Ngu K, Tino J, Kopcho LM, Lu H, Chen J, Tebben AJ, Sheriff S, Chang CY, Yanchunas J Jr, Calambur D, Gao M, Shuster DJ, Susulic V, Xie JH, Guarino VR, Wu DR, Gregor KR, Goldstine CB, Hynes J Jr, Macor JE, Salter-Cid L, Burke JR, Shaw PJ, Dhar TGM J Med Chem. 2020 Dec 1. doi: 10.1021/acs.jmedchem.0c01732. PMID:33261314 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tumor necrosis factor 3D structures

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