Ab initio molecular simulations for proposing potent inhibitors to butyrylcholinesterases

Murakawa, Takeru; Matsushita, Yuki; Suzuki, Tomoya; Khan, Mahmud Tareq Hassan; Kurita, Noriyuki

doi:10.1016/j.jmgm.2014.09.002

Cited by 9 publications

(11 citation statements)

References 28 publications

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“…Similarly, at the BChE active site, 2 bound with Tyr332 within the anionic hinge that prevents choline from entering the enzyme cavity. A recent study by Murakawa et al 38 revealed that Phe329 is a common binding site for active BChE inhibitors. The authors also described that Asp70 in the hinge and Gly116 within the oxyanion cavity form another active site for BChE where inhibitors may bind.…”

Section: Discussionmentioning

confidence: 99%

Arylbenzofurans from the Root Bark of Morus alba as Triple Inhibitors of Cholinesterase, β-Site Amyloid Precursor Protein Cleaving Enzyme 1, and Glycogen Synthase Kinase-3β: Relevance to Alzheimer’s Disease

et al. 2019

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Cholinesterase, β-site amyloid precursor protein cleaving enzyme 1 (BACE1), and glycogen synthase kinase-3β (GSK-3β) are the three main enzymes responsible for the early onset of Alzheimer’s disease (AD). The main aim of the present study was to delineate and accentuate the triple-inhibitory potential of arylbenzofurans from Morus alba against these enzymes. Overall, the enzyme inhibition assays demonstrated the prominence of mulberrofuran D2 as an inhibitor of AChE, BChE, BACE1, and GSK-3β enzymes with IC 50 values of 4.61, 1.51, 0.73, and 6.36 μM, respectively. Enzyme kinetics revealed different modes of inhibition, and in silico modeling suggested that mulberrofuran D2 inhibited these enzymes with low binding energy through hydrophilic, hydrophobic, and π–cation interactions in the active site cavities. Similarly, in Aβ-aggregation assays, mulberrofuran D2 inhibited self-induced and AChE-induced Aβ aggregation in a concentration-dependent manner that was superior to reference drugs. These results suggest that arylbenzofurans from M. alba , especially mulberrofuran D2, are triple inhibitors of cholinesterase, BACE1, and GSK-3β and may represent a novel class of anti-AD drugs.

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Section: Discussionmentioning

confidence: 99%

Arylbenzofurans from the Root Bark of Morus alba as Triple Inhibitors of Cholinesterase, β-Site Amyloid Precursor Protein Cleaving Enzyme 1, and Glycogen Synthase Kinase-3β: Relevance to Alzheimer’s Disease

et al. 2019

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“…In a later study of six inhibitors binding to the same enzyme, they obtained a somewhat poorer correlation (R 2 = 0.72, without entropy correction), 290 and the correlation was even worse for the binding of four ligands to butylcholinesterase (still without any entropy correction), R 2 = 0.54. 291 Explicit water molecules have also been included in studies of the plasminogen activator 292 and the 2G12 antibody. 293 They often gave unrealistically large absolute binding energies, because fixed water molecules underestimate the electrostatic screening.…”

Section: Fmomentioning

confidence: 99%

“…They obtained a good correlation to the experimental data ( R 2 = 0.94), but the absolute affinities were ∼20 times larger than the experimental ones. In a later study of six inhibitors binding to the same enzyme, they obtained a somewhat poorer correlation ( R 2 = 0.72, without entropy correction), and the correlation was even worse for the binding of four ligands to butylcholinesterase (still without any entropy correction), R 2 = 0.54 . Explicit water molecules have also been included in studies of the plasminogen activator and the 2G12 antibody .…”

Section: Single-structure Approachesmentioning

confidence: 99%

Ligand-Binding Affinity Estimates Supported by Quantum-Mechanical Methods

2016

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One of the largest challenges of computational chemistry is calculation of accurate free energies for the binding of a small molecule to a biological macromolecule, which has immense implications in drug development. It is well-known that standard molecular-mechanics force fields used in most such calculations have a limited accuracy. Therefore, there has been a great interest in improving the estimates using quantum-mechanical (QM) methods. We review here approaches involving explicit QM energies to calculate binding affinities, with an emphasis on the methods, rather than on specific applications. Many different QM methods have been employed, ranging from semiempirical QM calculations, via density-functional theory, to strict coupled-cluster calculations. Dispersion and other empirical corrections are mandatory for the approximate methods, as well as large basis sets for the stricter methods. QM has been used for the ligand, for a few crucial groups around the ligand, for all the closest atoms (200-1000 atoms), or for the full receptor-ligand complex, but it is likely that with a proper embedding it might be enough to include all groups within ∼6 Å of the ligand. Approaches involving minimized structures, simulations of the end states of the binding reaction, or full free-energy simulations have been tested.

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“…In the healthy brain, acetylcholinesterase (AChE) is the most important enzyme regulating the level of ACh, while butyrylcholinesterase (BChE) plays a minor role [ 1 ]. It is therefore expected that if the hydrolysis of ACh by AChE and BChE is inhibited in the brain of an AD patient, the amount of ACh in the synapse will be significantly increased and the neurotransmission mechanism will be more fluid [ 9 ]. For this reason, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors such as galantamine, donepezil, and rivastigmine are used in the management of AD, and the inhibition of the two types of cholinesterase enzymes (AChE and BuChE) as remedial for such treatment [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Non-Alkaloid Cholinesterase Inhibitory Compounds from Natural Sources

et al. 2021

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Alzheimer’s disease (AD) is a severe neurodegenerative disorder of different brain regions accompanied by distresses and affecting more than 25 million people in the world. This progressive brain deterioration affects the central nervous system and has negative impacts on a patient’s daily activities such as memory impairment. The most important challenge concerning AD is the development of new drugs for long-term treatment or prevention, with lesser side effects and greater efficiency as cholinesterases inhibitors and the ability to remove amyloid-beta(Aβ) deposits and other related AD neuropathologies. Natural sources provide promising alternatives to synthetic cholinesterase inhibitors and many have been reported for alkaloids while neglecting other classes with potential cholinesterase inhibition. This review summarizes information about the therapeutic potential of small natural molecules from medicinal herbs, belonging to terpenoids, coumarins, and phenolic compounds, and others, which have gained special attention due to their specific modes of action and their advantages of low toxicity and high efficiency in the treatment of AD. Some show superior drug-like features in comparison to synthetic cholinesterase inhibitors. We expect that the listed phytoconstituents in this review will serve as promising tools and chemical scaffolds for the discovery of new potent therapeutic leads for the amelioration and treatment of Alzheimer’s disease.

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Ab initio molecular simulations for proposing potent inhibitors to butyrylcholinesterases

Cited by 9 publications

References 28 publications

Arylbenzofurans from the Root Bark of Morus alba as Triple Inhibitors of Cholinesterase, β-Site Amyloid Precursor Protein Cleaving Enzyme 1, and Glycogen Synthase Kinase-3β: Relevance to Alzheimer’s Disease

Arylbenzofurans from the Root Bark of Morus alba as Triple Inhibitors of Cholinesterase, β-Site Amyloid Precursor Protein Cleaving Enzyme 1, and Glycogen Synthase Kinase-3β: Relevance to Alzheimer’s Disease

Ligand-Binding Affinity Estimates Supported by Quantum-Mechanical Methods

Non-Alkaloid Cholinesterase Inhibitory Compounds from Natural Sources

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