Abstract
Acetylcholinesterase (AChE) is a good target in the design of new drugs for the treatment of Alzheimer’s disease. The currently known drugs -donepezil, galantamine and rivastignime- act as moderate AChE inhibitors. In the present study, we docked a newly synthesized arylpiperazine derivative 1-(3-(4-benzylpiperazin-1-yl)propyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (LA1) into rhAChE and identified its binding mode. The docking pose of the studied LA1 molecule depends of the protonated state of the nitrogen atom of the piperazine moiety where in the best scored poses, the xanthine moiety of LA1 is bound into the catalytic active site (CAS) of AChE, while the arylpiperazine fragment is placed into the peripheral binding site (PAS). The Ellman’s test confirmed the compound binding. LA1 has good permeability through the GIT and BBB assessed by PAMPA. LA1 is a prospective lead for AChE inhibition.
Highlights
The biological role of acetylcholinesterase (AChE) is termination of impulse transmission at cholinergic synapses by hydrolysis of the neurotransmitter acetylcholine (Barnard, 1974)
The aim of our study is to identify by molecular docking the possible binding conformations of a newly synthesized 1-(3-(4-benzylpiperazin-1-yl)propyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione bound with rhAChE
Good permeability was confirmed with a PAMPA tests
Summary
The biological role of acetylcholinesterase (AChE) is termination of impulse transmission at cholinergic synapses by hydrolysis of the neurotransmitter acetylcholine (Barnard, 1974). Many diseases are characterized by degeneration of the cholinergic system. Reversible AChE inhibitors are used in the treatment of various disorders such as Alzheimer’s disease, myasthenia gravis, glaucoma, bladder distention, etc. The cognitive, behavioural and motor disabilities that characterize these pathologies are correlated to cholinergic circuit dysfunction (Tata et al, 2014). The most commonly used inhibitors include the natural product galantamine, the semisynthetic rivastigmine and the synthetic donepezil. Organophosphorus compounds act as irreversible AChE inhibitors (Čolović et al, 2013)
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