5NAU
Torpedo californica acetylcholinesterase in complex with a non-chiral donepezil-like compound 20
Summary for 5NAU
| Entry DOI | 10.2210/pdb5nau/pdb |
| Descriptor | Acetylcholinesterase, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total) |
| Functional Keywords | alzheimer's disease, acetylcholinesterase, donepezil analogues, green chemistry, hydrolase |
| Biological source | Tetronarce californica (Pacific electric ray) |
| Cellular location | Isoform H: Cell membrane; Lipid-anchor, GPI- anchor. Isoform T: Cell membrane; Peripheral membrane protein: P04058 |
| Total number of polymer chains | 1 |
| Total formula weight | 63537.25 |
| Authors | Caliandro, R.,Pesaresi, A.,Lamba, D. (deposition date: 2017-02-28, release date: 2018-05-02, Last modification date: 2024-10-23) |
| Primary citation | Caliandro, R.,Pesaresi, A.,Cariati, L.,Procopio, A.,Oliverio, M.,Lamba, D. Kinetic and structural studies on the interactions of Torpedo californica acetylcholinesterase with two donepezil-like rigid analogues. J Enzyme Inhib Med Chem, 33:794-803, 2018 Cited by PubMed Abstract: Acetylcholinesterase inhibitors were introduced for the symptomatic treatment of Alzheimer's disease (AD). Among the currently approved inhibitors, donepezil (DNP) is one of the most preferred choices in AD therapy. The X-ray crystal structures of Torpedo californica AChE in complex with two novel rigid DNP-like analogs, compounds 1 and 2, have been determined. Kinetic studies indicated that compounds 1 and 2 show a mixed-type inhibition against TcAChE, with K values of 11.12 ± 2.88 and 29.86 ± 1.12 nM, respectively. The DNP rigidification results in a likely entropy-enthalpy compensation with solvation effects contributing primarily to AChE binding affinity. Molecular docking evidenced the molecular basis for the binding of compounds 1 and 2 to the active site of β-secretase-1. Overall, these simplified DNP derivatives may represent new structural templates for the design of lead compounds for a more effective therapeutic strategy against AD by foreseeing a dual AChE and BACE-1 inhibitory activity. PubMed: 29651884DOI: 10.1080/14756366.2018.1458030 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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