4W63
TORPEDO CALIFORNICA ACETYLCHOLINESTERASE IN COMPLEX WITH A TACRINE-BENZOFURAN HYBRID INHIBITOR
Summary for 4W63
| Entry DOI | 10.2210/pdb4w63/pdb |
| Descriptor | Acetylcholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total) |
| Functional Keywords | multitarget drug, enzyme-inhibitor complex, tacrine, benzofuran, hydrolase |
| Biological source | Torpedo californica (Pacific electric ray) |
| Total number of polymer chains | 1 |
| Total formula weight | 61755.64 |
| Authors | Pesaresi, A.,Samez, S.,Lamba, D. (deposition date: 2014-08-20, release date: 2015-09-09, Last modification date: 2024-11-13) |
| Primary citation | Zha, X.,Lamba, D.,Zhang, L.,Lou, Y.,Xu, C.,Kang, D.,Chen, L.,Xu, Y.,Zhang, L.,De Simone, A.,Samez, S.,Pesaresi, A.,Stojan, J.,Lopez, M.G.,Egea, J.,Andrisano, V.,Bartolini, M. Novel Tacrine-Benzofuran Hybrids as Potent Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and X-ray Crystallography. J.Med.Chem., 59:114-131, 2016 Cited by PubMed Abstract: Twenty-six new tacrine-benzofuran hybrids were designed, synthesized, and evaluated in vitro on key molecular targets for Alzheimer's disease. Most hybrids exhibited good inhibitory activities on cholinesterases and β-amyloid self-aggregation. Selected compounds displayed significant inhibition of human β-secretase-1 (hBACE-1). Among the 26 hybrids, 2e showed the most interesting profile as a subnanomolar selective inhibitor of human acetylcholinesterase (hAChE) (IC50 = 0.86 nM) and a good inhibitor of both β-amyloid aggregation (hAChE- and self-induced, 61.3% and 58.4%, respectively) and hBACE-1 activity (IC50 = 1.35 μM). Kinetic studies showed that 2e acted as a slow, tight-binding, mixed-type inhibitor, while X-ray crystallographic studies highlighted the ability of 2e to induce large-scale structural changes in the active-site gorge of Torpedo californica AChE (TcAChE), with significant implications for structure-based drug design. In vivo studies confirmed that 2e significantly ameliorates performances of scopolamine-treated ICR mice. Finally, 2e administration did not exhibit significant hepatotoxicity. PubMed: 26632651DOI: 10.1021/acs.jmedchem.5b01119 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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