Abstract:Due to the diversity of biological activities that can be found in aquatic ecosystems, marine metabolites have been an active area of drug discovery for the last 30 years. Marine metabolites have been found to inhibit a number of enzymes important in the treatment of human disease. Here, we focus on marine metabolites that inhibit the enzyme acetylcholinesterase, which is the cellular target for treatment of early-stage Alzheimer’s disease. Currently, development of anticholinesterase drugs with improved poten… Show more
“…It has been extensively reported that π–π interactions with Tyr84 and Phe330 restrict the entry of substrates into the acyl pocket. Inhibition of AchE from tacrine is also mediated by a similar interaction with Phe330 [42, 43]. Fig.…”
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.
“…It has been extensively reported that π–π interactions with Tyr84 and Phe330 restrict the entry of substrates into the acyl pocket. Inhibition of AchE from tacrine is also mediated by a similar interaction with Phe330 [42, 43]. Fig.…”
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.
“…Based on a recent comprehensive survey about anti‐AChE marine metabolites (Stoddard et al . ), only seven different classes of marine metabolites, a sesquiterpene acetate isolated from the mucous secretion of the Onchidella binneyi mollusk (Ireland and Faulkner ), a pyrrole derivative isolated from the gliding bacteria Rapidithrix thailandica (Sangnoi et al . ), a tetrazacyclopentazulene isolated from zoanthid corals (Turk et al .…”
This study highlights that exploring new lead anti-AChE compounds may result in discovering novel adjuvant candidates with potency in the treatment of cognitive diseases such as AD.
“…Docking predicted the binding at the hydrophobic Val18_Phe20 channel on the flat surface of Aβ fiber and act as an efficient tracer [59]. Docking and simulation studies have been successfully applied to identify both acetylcholinesterase activity and amyloid-β aggregation inhibitors from marine metabolites [60]. Computationally designed peptide inhibitors and mutational analysis suggested that GxMxG motif is the major factor creating the compatibility between two amyloid surfaces [58].…”
Alzheimer disease (AD) is now considered as a multifactorial neurodegenerative disorder and rapidly increasing to an alarming situation and causing higher death rate. One target one ligand hypothesis does not provide complete solution of AD due to multifactorial nature of the disease and one target one drug fails to provide better treatment against AD. Moreover, currently available treatments are limited and most of the upcoming treatments under clinical trials are based on modulating single target. So, the current AD drug discovery research is shifting towards a new approach for a better solution that simultaneously modulates more than one targets in the neurodegenerative cascade. This can be achieved by network pharmacology, multi-modal therapies, multifaceted, and/or the more recently proposed term "multi-targeted designed drugs". Drug discovery project is a tedious, costly and long-term project. Moreover, multi-target AD drug discovery added extra challenges such as the good binding affinity of ligands for multiple targets, optimal ADME/T properties, no/less off-target side effect and crossing of the blood-brain barrier. These hurdles may be addressed by insilico methods for an efficient solution in less time and cost as computational methods successfully applied to single target drug discovery project. Here, we are summarizing some of the most prominent and computationally explored single targets against AD and further, we discussed a successful example of dual or multiple inhibitors for same targets. Moreover, we focused on ligand and structure-based computational approach to design MTDL against AD. However, it is not an easy task to balance dual activity in a single molecule but computational approach such as virtual screening docking, QSAR, simulation and free energy is useful in future MTDLs drug discovery alone or in combination with a fragment-based method. However, rational and logical implementations of computational drug designing methods are capable of assisting AD drug discovery and play an important role in optimizing multi-target drug discovery.
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