7amz

Crystal structure of human Butyrylcholinesterase in complex with N-((2S,3R)-4-((2,2-dimethylpropyl)amino)-3-hydroxy-1-phenylbutan-2-yl)-2,2-diphenylacetamide

spinqualitylabelsall models 7amz, resolution 2.25Å 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 2.25Å Ligands: FUC, GOL, MES, NAG, RNZ, SIA, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Looking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: beta-secretase enzyme (BACE1) and amyloid beta (Abeta) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and gamma-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50 = 2.86 muM; eqBuChE IC50 = 60 nM; hBuChE IC50 = 20 nM; hBACE1 IC50 = 5.9 muM; inhibition of Abeta aggregation = 57.9% at 10 muM; mGAT1 IC50 = 10.96 muM; and mGAT2 IC50 = 19.05 muM). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50 = 5.01 muM and IC50 = 2.95 muM, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease. Discovery of multifunctional anti-Alzheimer's agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and gamma-aminobutyric acid transporters.,Pasieka A, Panek D, Jonczyk J, Godyn J, Szalaj N, Latacz G, Tabor J, Mezeiova E, Chantegreil F, Dias J, Knez D, Lu J, Pi R, Korabecny J, Brazzolotto X, Gobec S, Hofner G, Wanner K, Wieckowska A, Malawska B Eur J Med Chem. 2021 Jun 5;218:113397. doi: 10.1016/j.ejmech.2021.113397. Epub, 2021 Mar 31. PMID:33838585 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Butyrylcholinesterase 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA