7AWI
Crystal structure of human butyrylcholinesterase in complex with tert-butyl 3-(((2-((1-benzyl-1H-indol-4-yl)oxy)ethyl)amino)methyl]piperidine-1-carboxylate
Summary for 7AWI
| Entry DOI | 10.2210/pdb7awi/pdb |
| Descriptor | Cholinesterase, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total) |
| Functional Keywords | butyrylcholinesterase, inhibitor complex, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 63017.80 |
| Authors | Brazzolotto, X.,Goral, I.,Wieckowska, A. (deposition date: 2020-11-08, release date: 2021-09-29, Last modification date: 2024-11-13) |
| Primary citation | Wichur, T.,Godyn, J.,Goral, I.,Latacz, G.,Bucki, A.,Siwek, A.,Gluch-Lutwin, M.,Mordyl, B.,Sniecikowska, J.,Walczak, M.,Knez, D.,Jukic, M.,Salat, K.,Gobec, S.,Kolaczkowski, M.,Malawska, B.,Brazzolotto, X.,Wieckowska, A. Development and crystallography-aided SAR studies of multifunctional BuChE inhibitors and 5-HT 6 R antagonists with beta-amyloid anti-aggregation properties. Eur.J.Med.Chem., 225:113792-113792, 2021 Cited by PubMed Abstract: The lack of an effective treatment makes Alzheimer's disease a serious healthcare problem and a challenge for medicinal chemists. Herein we report interdisciplinary research on novel multifunctional ligands targeting proteins and processes involved in the development of the disease: BuChE, 5-HT receptors and β-amyloid aggregation. Structure-activity relationship analyses supported by crystallography and docking studies led to the identification of a fused-type multifunctional ligand 50, with remarkable and balanced potencies against BuChE (IC = 90 nM) and 5-HTR (K = 4.8 nM), and inhibitory activity against Aβ aggregation (53% at 10 μM). In in vitro ADME-Tox and in vivo pharmacokinetic studies compound 50 showed good stability in the mouse liver microsomes, favourable safety profile and brain permeability with the brain to plasma ratio of 6.79 after p.o. administration in mice, thus being a promising candidate for in vivo pharmacology studies and a solid foundation for further research on effective anti-AD therapies. PubMed: 34530376DOI: 10.1016/j.ejmech.2021.113792 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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