Novel cannabidiol−carbamate hybrids as selective BuChE inhibitors: Docking-based fragment reassembly for the development of potential therapeutic agents against Alzheimer's disease

Jiang, Xia; Zhang, Ziwen; Zuo, Jiawei; Wu, Chengyao; Zha, Liang; Xu, Yingying; Wang, Sheng; Shi, Jing; Liu, Xinhua; Zhang, Jing; Tang, Wenjian

doi:10.1016/j.ejmech.2021.113735

Cited by 35 publications

(24 citation statements)

References 64 publications

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“…The new cannabidiol−carbamate hybrid lead compound (namely, C16) exhibits a much stronger inhibition of butyrylcholinesterase (BuChE) (IC 50 = 5.3 nM) than that of CBD (IC 50 = 0.67 μM) and crosses the BBB. Authors have demonstrated that C16 is able to improve scopolamine-induced cognition impairment in mice, and the treated mice exhibit better behavioral activity than donepezil ( Jiang et al, 2021 ). Contrary to other observations, Amini et al have reported that CBD, when delivered using chitosan nanoparticles, reduces Aβ plaque formation and learning and memory in AD-bearing rats via enhancing the expression levels of CB1 and CB2, though the effect of empty chitosan NPs on CB1 and CB2 has not been investigated in this study ( Amini and Abdolmaleki, 2021 ).…”

Section: Disease-specific Pathwaymentioning

confidence: 99%

Cannabidiol for neurodegenerative disorders: A comprehensive review

et al. 2022

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Despite the significant advances in neurology, the cure for neurodegenerative conditions remains a formidable task to date. Among various factors arising from the complex etiology of neurodegenerative diseases, neuroinflammation and oxidative stress play a major role in pathogenesis. To this end, some phytocannabinoids isolated from Cannabis sativa (widely known as marijuana) have attracted significant attention as potential neurotherapeutics. The profound effect of ∆9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, has led to the discovery of the endocannabinoid system as a molecular target in the central nervous system (CNS). Cannabidiol (CBD), the major non-psychoactive component of cannabis, has recently emerged as a potential prototype for neuroprotective drug development due to its antioxidant and anti-inflammatory properties and its well-tolerated pharmacological behavior. This review briefly discusses the role of inflammation and oxidative stress in neurodegeneration and demonstrates the neuroprotective effect of cannabidiol, highlighting its general mechanism of action and disease-specific pathways in Parkinson’s disease (PD) and Alzheimer’s disease (AD). Furthermore, we have summarized the preclinical and clinical findings on the therapeutic promise of CBD in PD and AD, shed light on the importance of determining its therapeutic window, and provide insights into identifying promising new research directions.

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Section: Disease-specific Pathwaymentioning

confidence: 99%

Cannabidiol for neurodegenerative disorders: A comprehensive review

et al. 2022

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“…According to some in vitro studies, CBD increases the Aβ amyloid protein’s proteolytic pathway on SHY5YAPP+ cells (a neuroblastoma cell line) by inducing APP ubiquitination, which boosts cell viability [ 60 ]. Ethyl, which is a functional group in cannabinol C2 and is similar to Galantamine, can effectively enter the active pocket of AChE [ 61 ].Furthermore, THCV consist of Enol as a functional group that might be identified to break up amyloid plaques and enhance the rapid clearance of toxic aggregates in AD which is relatively similar to keto-enol pharmacophores [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Investigation of Cannabis sativa Phytochemicals as Anti-Alzheimer’s Agents: An In Silico Study

Patil

Chandel

Rana

et al. 2023

Plants

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Cannabis sativa is a medicinal plant that has been known for years and is used as an Ayurvedic medicine. This plant has great potential in treating various types of brain diseases. Phytochemicals present in this plant act as antioxidants by maintaining synaptic plasticity and preventing neuronal loss. Cannabidiol (CBD) and Tetrahydrocannabinol (THC) are both beneficial in treating Alzheimer’s disease by increasing the solubility of Aβ42 amyloid and Tau aggregation. Apart from these therapeutic effects, there are certain unknown functions of these phytochemicals in Alzheimer’s disease that we want to elucidate through this study. In this research, our approach is to analyze the effect of phytochemicals in Cannabis sativa on multiple culprit enzymes in Alzheimer’s disease, such as AChE (Acetylcholinesterase), BChE (Butyrylcholinesterase), γ-secretase, and BACE-1. In this study, the compounds were selected by Lipinski’s rule, ADMET, and ProTox based on toxicity. Molecular docking between the selected compounds (THCV, Cannabinol C2, and Cannabidiorcol) and enzymes mentioned above was obtained by various software programs including AutoDock Vina 4.2, AutoDock, and iGEMDOCK. In comparison to Donepezil (BA = −8.4 kcal/mol, Ki = 1.46 mM), Rivastigmine (BA = −7.0 kcal/mol, Ki = 0.02 mM), and Galantamine (BA = −7.1, Ki = 2.1 mM), Cannabidiorcol (BA = −9.4 kcal/mol, Ki = 4.61 mM) shows significant inhibition of AChE. On the other hand, Cannabinol C2 (BA = −9.2 kcal/mol, Ki = 4.32 mM) significantly inhibits Butyrylcholinesterase (BuChE) in comparison to Memantine (BA = −6.8 kcal/mol, Ki = 0.54 mM). This study sheds new light and opens new avenues for elucidating the role of bioactive compounds present in Cannabis sativa in treating Alzheimer’s disease.

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“…The molecular dynamics (MD) simulations were performed in Yinfo Cloud Computing Platform using AmberTools 20 package with AMBER ff19SB and GAFF force fields for NorA and compound 2e , respectively. 21,22 The system was solvated by a truncated octahedron (or cubic) water box using OPC water model with a margin of 10 Å, the net charge was neutralized by (0.15 M of NaCl) sodium ions. Periodic boundary condition (PBC) was used and the net charge neutralized by Na + (or Cl − ) ions (or 0.15 M of NaCl).…”

Section: Methodsmentioning

confidence: 99%