6TT0

Crystal structure of a potent and reversible dual binding site Acetylcholinesterase chiral inhibitor

Summary for 6TT0

• Entry DOI: 10.2210/pdb6tt0/pdb
• Descriptor: Acetylcholinesterase, (1~{R},3~{S})-~{N}-(6,7-dimethoxy-2-oxidanylidene-chromen-3-yl)-3-[(phenylmethyl)amino]cyclohexane-1-carboxamide, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: dual binding site inhibitor, chiral separation, acetylcholinesterase, alzheimer's disease, hydrolase
• Biological source: Tetronarce californica (Pacific electric ray)
• Total number of polymer chains: 1
• Total formula weight: 66194.51

Authors

de la Mora, E.,Mangiatordi, G.F.,Belviso, B.D.,Caliandro, R.,Colletier, J.P.,Catto, M. (deposition date: 2019-12-22, release date: 2020-06-10, Last modification date: 2024-11-20)

Primary citation

Catto, M.,Pisani, L.,de la Mora, E.,Belviso, B.D.,Mangiatordi, G.F.,Pinto, A.,Palma, A.,Denora, N.,Caliandro, R.,Colletier, J.P.,Silman, I.,Nicolotti, O.,Altomare, C.D.
Chiral Separation, X-ray Structure, and Biological Evaluation of a Potent and Reversible Dual Binding Site AChE Inhibitor.
Acs Med.Chem.Lett., 11:869-876, 2020

PubMed Abstract: Acetylcholinesterase (AChE) inhibitors (AChEIs) still remain the leading therapeutic options for the symptomatic treatment of cognitive deficits associated with mild-to-moderate Alzheimer's disease. The search for new AChEIs benefits from well-established knowledge of the molecular interactions of selective AChEIs, such as donepezil and related dual binding site inhibitors. Starting from a previously disclosed coumarin-based inhibitor (±)--, active as racemate in the nanomolar range toward AChE, we proceeded on a double track by (i) achieving chiral resolution of the enantiomers of by HPLC and (ii) preparing two close achiral analogues of , i.e., compounds and . An eudismic ratio as high as 20 was observed for the (-) enantiomer of -. The X-ray crystal structure of the complex between the (-)-- eutomer (coded as ) and AChE was determined at 2.8 Å, and docking calculation results suggested that the eutomer in (1,3) absolute configuration should be energetically more favored in binding the enzyme than the eutomer in (1,3) configuration. The achiral analogues and were less effective in inhibiting AChE compared to (±)--, but interestingly butylamide emerged as a potent inhibitor of butyrylcholinesterase (BChE).

PubMed: 32435398
DOI: 10.1021/acsmedchemlett.9b00656

Experimental method

X-RAY DIFFRACTION (2.80003021833 Å)