Phenoxyethyl Piperidine/Morpholine Derivatives as PAS and CAS Inhibitors of Cholinesterases: Insights for Future Drug Design

Abstract

Acetylcholinesterase (AChE) catalyzes the conversion of Aβ peptide to its aggregated form and the peripheral anionic site (PAS) of AChE is mainly involved in this phenomenon. Also catalytic active site (CAS) of donepezil stimulates the break-down of acetylcholine (ACh) and depletion of ACh in cholinergic synapses are well established in brains of patients with AD. In this study, a set of compounds bearing phenoxyethyl amines were synthesized and their inhibitory activity toward electric eel AChE (eeAChE) and equine butyrylcholinesterase (eqBuChE) were evaluated. Molecular dynamics (MD) was employed to record the binding interactions of best compounds against human cholinesterases (hAChE and hBuChE) as well as donepezil as reference drug. In vitro results revealed that compound 5c is capable of inhibiting eeAChE activity at IC50 of 0.50 µM while no inhibitory activity was found for eqBuChE for up to 100 µM concentrations. Compound 5c, also due to its facile synthesis, small structure and high selectivity for eeAChE would be very interesting candidate in forthcoming studies. The main interacting parts of compound 5c and compound 7c (most potent eeAChE and eqBuChE inhibitors respectively) with receptors which confer selectivity for AChE and BuChE inhibition were identified, discussed, and compared with donepezil’s interactions. Also during MD simulation it was discovered for the first time that binding of substrates like donepezil to dual CAS and PAS or solely CAS region might have a suppressive impact on 4-α-helical bundles near the tryptophan amphiphilic tetramerization (WAT) domain of AChE and residues which are far away from AChE active site. The results proposed that residues involved in donepezil interactions (Trp86 and Phe295) which are located in CAS and mid-gorge are the mediator of conformational changes in whole protein structure.

Exploring the out of sight antigens of SARS-CoV-2 to design a candidate multi-epitope vaccine by utilizing immunoinformatics approaches

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Phlorotannins as HIV Vpu inhibitors, an in silico virtual screening study of marine natural products

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A Comprehensive Review of Cholinesterase Modeling and Simulation

“…As a reminder, compounds are placed in this section due to the general abundance or consistent occurrence of amine groups in the inhibitor series studied in a given paper. For example, piperidine is an amine-containing compound that has been considered as a cholinesterase inhibitor in a handful of publications, including phenoxyethyl piperidine derivatives, which were studied via MD simulation in complex with electric eel AChE and horse BChE [ 178 ]. The phenoxyethyl derivatives most structurally similar to donepezil had the ability to bind to both the CAS and PAS, while many others bound only to the CAS [ 178 ].…”

“…For example, piperidine is an amine-containing compound that has been considered as a cholinesterase inhibitor in a handful of publications, including phenoxyethyl piperidine derivatives, which were studied via MD simulation in complex with electric eel AChE and horse BChE [ 178 ]. The phenoxyethyl derivatives most structurally similar to donepezil had the ability to bind to both the CAS and PAS, while many others bound only to the CAS [ 178 ]. In contrast, piperidine compounds substituted with arylaminopropanone were recently examined by Hudcova et al via docking, MD, and QM/MM approaches and were compared to rivastigmine and galantamine [ 179 ].…”