8xgv | pdb_00008xgv

Optimization Efforts for Identification of Novel Highly Potent Keap1-Nrf2 Protein-Protein Interaction (PPI) Inhibitors

spinqualitylabelsall models 8xgv, resolution 1.42Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8xgv is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.42Å Ligands: A1LVC, ACT, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KEAP1_HUMAN Publication Abstract from PubMed In research focused on protein-protein interaction (PPI) inhibitors, the optimization process to achieve both high inhibitory activity and favorable physicochemical properties remains challenging. Our previous study reported the discovery of novel and bioavailable Keap1-Nrf2 PPI inhibitor 8 which exhibited moderate in vivo activity in rats. In this work, we present our subsequent efforts to optimize this compound. Two distinct approaches were employed, targeting high energy water molecules and Ser602 as "hot spots" from the anchor with good aqueous solubility, metabolic stability, and membrane permeability. Through ligand efficiency (LE)-guided exploration, we identified two novel inhibitors 22 and 33 with good pharmacokinetics (PK) profiles and more potent in vivo activities, which appear to be promising chemical probes among the existing inhibitors. Optimization Efforts for Identification of Novel Highly Potent Keap1-Nrf2 Protein-Protein Interaction Inhibitors.,Otake K, Hara Y, Ubukata M, Inoue M, Nagahashi N, Motoda D, Ogawa N, Hantani Y, Hantani R, Adachi T, Nomura A, Yamaguchi K, Maekawa M, Mamada H, Motomura T, Sato M, Harada K J Med Chem. 2024 Mar 14;67(5):3741-3763. doi: 10.1021/acs.jmedchem.3c02171. Epub , 2024 Feb 26. PMID:38408347 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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