Coumarin derivatives as acetyl- and butyrylcholinestrase inhibitors: An in vitro, molecular docking, and molecular dynamics simulations study

Abstract

Alzheimer's disease is an irreversible and progressive brain disease that can cause problems with memory and thinking skills. It is characterized by loss of cognitive ability and severe behavioral abnormalities, and could lead to death. Cholinesterases (ChEs) play a crucial role in the control of cholinergic transmission, and subsequently, the acetylcholine level in the brain is upgraded by inhibition of ChEs. Coumarins have been shown to display potential cholinesterase inhibitory action, where the aromatic moiety has led to the design of new candidates that could inhibit Aβ aggregation. Accordingly, the present work is an in vitro activity, along with docking and molecular dynamics (MD) simulation studies of synthesized coumarin derivatives, to explore the plausible binding mode of these compounds inside the cholinesterase enzymes. For this purpose, a series of previously prepared N1 -(coumarin-7-yl) derivatives were screened in vitro for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. The assayed compounds exhibited moderate inhibitory activity against AChE, with IC 50 values ranging from 42.5 ± 2.68 to 442 ± 3.30 μM. On the other hand, the studied compounds showed remarkable activity against BChE with IC 50 values ranging from 2.0 ± 1.4 nM to 442 ± 3.30 μM. In order to better understand the ligand binding site interaction of compounds and the stability of protein-ligand complexes, a molecular docking with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for both cholinesterases. We concluded that the tested coumarin derivatives are potential candidates as leads for potent and efficacious ChEs inhibitors.

Recent Advances in the Synthesis and Biological Activity of 8-Hydroxyquinolines

“…This disease is becoming a universal health problem, and it can eventually lead to death [ 48 ]. Statistics indicate the presence of approximately 2.5 to 4.0 million Alzheimer’s disease patients in the United States, and 17 and 25 million worldwide [ 49 ]. Published research findings indicate that cholinergic dysfunction could be associated with selective and irreversible deficiency of the neurotransmitter acetylcholine, which is controlled by hydrolysis of acetylcholine via acetylcholinestrase (AChE) and butyrylcholinestrase (BChE).…”

“…Published research findings indicate that cholinergic dysfunction could be associated with selective and irreversible deficiency of the neurotransmitter acetylcholine, which is controlled by hydrolysis of acetylcholine via acetylcholinestrase (AChE) and butyrylcholinestrase (BChE). Additionally, it was suggested that AChE predominates in a healthy brain, whereas BChE is considered to play a minor role in regulating the brain’s ACh levels [ 49 ].…”

Identification of ovalbumin‐derived peptides as multi‐target inhibitors of AChE, BChE, and BACE1

“…The Asp70 residue interacts with the tripeptide CIK by two salt bridges and a carbon‐hydrogen bond, and Tyr332 residue forms a conventional hydrogen bond and a pi‐alkyl with the tripeptide CIK. These two residues are essential for substrate‐enzyme binding . The interaction between CIK and BACE1 involves the following amino acid residues: Ile110, Thr232, Gly230, Thr231, Arg235, Thr72, Gly34, Asp228, and Asp32 (shown in Fig.…”

“…These two residues are essential for substrate-enzyme binding. 34 The interaction between CIK and BACE1 involves the following amino acid residues: Ile110, Thr232, Gly230, Thr231, Arg235, Thr72, Gly34, Asp228, and Asp32 (shown in Fig. 4).…”

Inhibition of Butyrylcholinesterase and Human Monoamine Oxidase-B by the Coumarin Glycyrol and Liquiritigenin Isolated from Glycyrrhiza uralensis

“…Jannat et al reported that (2 S ,3 R )-pretosin C is a noncompetitive inhibitor of BChE and that it hydrophobically interacts with Val288, Lue286, and Phe357, and hydrogen bonds with Gly283 and Asn397, and docks at a non-ligand binding site [ 56 ]. It was also observed that hydrogen bond formation was the main driving force behind BChE–coumarin complex formation, whereas hydrophobic and halogen interactions underpinned AChE interactions with N 1-(coumarin-7-yl) derivatives [ 57 ]. Similarly, we found that GC hydrogen bonded with Thr284 and Val288 located outside the ligand binding site.…”