Galantamine Derivatives as Acetylcholinesterase Inhibitors: Docking, Design, Synthesis, and Inhibitory Activity

Doytchinova, Irini; Atanasova, Mariyana; Stavrakov, Georgi; Philipova, Irena; Zheleva‐Dimitrova, Dimitrina

doi:10.1007/978-1-4939-7404-7_6

Cited by 6 publications

(5 citation statements)

References 51 publications

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“…About 150,000 NCs available in 11 databases at ZINC12 were subject to virtual screening via molecular docking against AChE. The applied docking protocol was previously optimized and used to predict new AChE inhibitors that were experimentally proven [ 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. The compounds were screened for BBB permeability, drug-likeness filters, GI absobtion, PAINS, and lead-likeness.…”

Section: Discussionmentioning

confidence: 99%

“…The structures were docked into the X-ray structure of recombinant human acetylcholinesterase (rhAChE, pdb id: 4EY6, R = 2.40 Å) [ 6 ]. The docking simulations were performed with GOLD v.5.2.2 [CCDC Ltd., Cambridge, UK] using a previously described and optimized-for-this-system protocol [ 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. The following settings were used: scoring function ChemPLP, rigid protein, flexible ligand, and a radius of the binding site of 6 Å around the crystallographic structure of GAL.…”

Section: Methodsmentioning

confidence: 99%

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Virtual Screening and Hit Selection of Natural Compounds as Acetylcholinesterase Inhibitors

et al. 2022

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Acetylcholinesterase (AChE) is one of the classical targets in the treatment of Alzheimer’s disease (AD). Inhibition of AChE slows down the hydrolysis of acetycholine and increases choline levels, improving the cognitive function. The achieved success of plant-based natural drugs acting as AChE inhibitors, such as galantamine (GAL) from Galanthus genus and huperzine A from Huperzia serrate (approved drug in China), in the treatment of AD, and the fact that natural compounds (NCs) are considered as safer and less toxic compared to synthetic drugs, led us to screen the available NCs (almost 150,000) in the ZINC12 database for AChE inhibitory activity. The compounds were screened virtually by molecular docking, filtered for suitable ADME properties, and 32 ligands from 23 structural groups were selected. The stability of the complexes was estimated via 1 μs molecular dynamics simulation. Ten compounds formed stable complexes with the enzyme and had a vendor and a reasonable price per mg. They were tested for AChE inhibitory and antioxidant activity. Five compounds showed weak AChE inhibition and three of them exhibited high antioxidant activity.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Virtual Screening and Hit Selection of Natural Compounds as Acetylcholinesterase Inhibitors

et al. 2022

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“…It was first discovered in 1952 as a tertiary alkaloid. Memory loss and cognitive impairment in Alzheimer’s patients may be treated with AChE inhibitors . Galantamine was the subject of seven large-scale, placebo-controlled investigations in people with AD.…”

Section: Plant Materials and Derived Phytochemicals For Treatment Of Admentioning

confidence: 99%

“…Memory loss and cognitive impairment in Alzheimer’s patients may be treated with AChE inhibitors. 162 Galantamine was the subject of seven large-scale, placebo-controlled investigations in people with AD. Galantamine was shown to be both safe and effective in these investigations.…”

Section: Plant Materials and Derived Phytochemicals For Treatment Of Admentioning

confidence: 99%

Synthetic and Natural Bioactive Molecules in Balancing the Crosstalk among Common Signaling Pathways in Alzheimer’s Disease: Understanding the Neurotoxic Mechanisms for Therapeutic Intervention

Shah,

Mir,

Adnan

et al. 2023

ACS Omega

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The structure and function of the brain greatly rely on different signaling pathways. The wide variety of biological processes, including neurogenesis, axonal remodeling, the development and maintenance of pre- and postsynaptic terminals, and excitatory synaptic transmission, depends on combined actions of these molecular pathways. From that point of view, it is important to investigate signaling pathways and their crosstalk in order to better understand the formation of toxic proteins during neurodegeneration. With recent discoveries, it is established that the modulation of several pathological events in Alzheimer’s disease (AD) due to the mammalian target of rapamycin (mTOR), Wnt signaling, 5′-adenosine monophosphate activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), and sirtuin 1 (Sirt1, silent mating-type information regulator 2 homologue 1) are central to the key findings. These include decreased amyloid formation and inflammation, mitochondrial dynamics control, and enhanced neural stability. This review intends to emphasize the importance of these signaling pathways, which collectively determine the fate of neurons in AD in several ways. This review will also focus on the role of novel synthetic and natural bioactive molecules in balancing the intricate crosstalk among different pathways in order to prolong the longevity of AD patients.

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“…Due to this variety of actions, GAL can serve as а multitarget scaffold to design new derivatives with a higher AChE inhibitory effect and lower toxicity. Steadily in recent decades, GAL is the focus of many lab projects around the world aiming to develop safer and more powerful anti-neurodegenerative agents [17][18][19][20][21][22][23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening

et al. 2021

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Despite extensive and intensive research efforts in recent decades, there is still no effective treatment for neurodegenerative diseases. On this background, the use of drugs inhibiting the enzyme acetylcholinesterase (AChE) remains an eternal evergreen in the symptomatic treatment of mild to moderate cognitive impairments. Even more, the cholinergic hypothesis, somewhat forgotten in recent years due to the shift in focus on amyloid cascade, is back to life, and the search for new, more effective AChE inhibitors continues. We generated a fragment-based library containing aromatic moieties and linkers originating from a set of novel AChE inhibitors. We used this library to design 1220 galantamine (GAL) derivatives following the model GAL (binding core) - linker (L) - aromatic fragment (Ar). The newly designed compounds were screened virtually for blood–brain barrier (BBB) permeability and binding to AChE. Among the top 10 best-scored compounds, a representative lead molecule was selected and tested for anti-AChE activity and neurotoxicity. It was found that the selected compound was a powerful non-toxic AChE inhibitor, 68 times more active than GAL, and could serve as a lead molecule for further optimization and development.

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Galantamine Derivatives as Acetylcholinesterase Inhibitors: Docking, Design, Synthesis, and Inhibitory Activity

Cited by 6 publications

References 51 publications

Virtual Screening and Hit Selection of Natural Compounds as Acetylcholinesterase Inhibitors

Virtual Screening and Hit Selection of Natural Compounds as Acetylcholinesterase Inhibitors

Synthetic and Natural Bioactive Molecules in Balancing the Crosstalk among Common Signaling Pathways in Alzheimer’s Disease: Understanding the Neurotoxic Mechanisms for Therapeutic Intervention

Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening

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