Rational design and synthesis of highly potent anti-acetylcholinesterase activity huperzine A derivatives

Jian, Yan; Sun, Lirong; Wu, Guisheng; Yi, Ping; Yang, Fu‐Mei; Zhou, Lin; Zhang, Xianmin; Li, Zhongrong; Xiao-sheng, Yang; Luo, Huai‐Rong; Qiu, Ming‐Hua

doi:10.1016/j.bmc.2009.08.017

Cited by 19 publications

(17 citation statements)

References 41 publications

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“…Novel donepezil-tacrine and oxoisoaporphine-tacrine congeners hybrid related derivatives, coumarin and huperzine A derivatives have exhibited high AChE inhibitory activity with IC 50 values in the nanomolar range, and ability to bind simultaneously to both peripheral and catalytic sites of the enzyme. For the reason, these dual binding site inhibitors are promising compounds for developing disease-modifying drugs for the future treatment of AD [58-62], Additionally, new synthesized symmetrical bispyridinium and carbamate anti-AChE compounds inhibit the enzyme in micromolar concentrations, making them the potential candidates for the treatment of AD [63, 64]. …”

Section: Acetylcholinesterase Inhibitorsmentioning

confidence: 99%

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

et al. 2013

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Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer’s disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases.

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Section: Acetylcholinesterase Inhibitorsmentioning

confidence: 99%

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

et al. 2013

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“…After the interaction, the magnetic particles can be easily pulled out using an outside magnetic field. But there is a possibility that the chemical conjugation may affect the binding characteristics of the compound [26]. Therefore it is very important to include binding experiments without the MPs to confirm the interaction between the drug itself and the possible targets (Figure 3 and 4).…”

Section: Discussionmentioning

confidence: 99%

“…For the tissue lysate study, we think there is a possibility that the amine group on Hup A that we used to link to the magnetic particles was critical for binding with AChE. Although most studies had suggested the lactam ring and ethylidene methyl [26] on Hup A were main binding moieties, an earlier study had suggested that there were interactions between the amine group of Hup A with the aromatic groups of Trp 84 and Phe 330 of AChE and also ionic interactions between the amine group with the carboxyl groups of Asp 72 and Glu 199 of AChE [30]. We had tried to look for bindings between Hup-MPs with pure AChE purchased from Sigma.…”

Section: Discussionmentioning

confidence: 99%

Examining the Interactome of Huperzine A by Magnetic Biopanning

et al. 2012

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Huperzine A is a bioactive compound derived from traditional Chinese medicine plant Qian Ceng Ta (Huperzia serrata), and was found to have multiple neuroprotective effects. In addition to being a potent acetylcholinesterase inhibitor, it was thought to act through other mechanisms such as antioxidation, antiapoptosis, etc. However, the molecular targets involved with these mechanisms were not identified. In this study, we attempted to exam the interactome of Huperzine A using a cDNA phage display library and also mammalian brain tissue extracts. The drugs were chemically linked on the surface of magnetic particles and the interactive phages or proteins were collected and analyzed. Among the various cDNA expressing phages selected, one was identified to encode the mitochondria NADH dehydrogenase subunit 1. Specific bindings between the drug and the target phages and target proteins were confirmed. Another enriched phage clone was identified as mitochondria ATP synthase, which was also panned out from the proteome of mouse brain tissue lysate. These data indicated the possible involvement of mitochondrial respiratory chain matrix enzymes in Huperzine A's pharmacological effects. Such involvement had been suggested by previous studies based on enzyme activity changes. Our data supported the new mechanism. Overall we demonstrated the feasibility of using magnetic biopanning as a simple and viable method for investigating the complex molecular mechanisms of bioactive molecules.

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“…There are 17 chemical-protein interaction pairs validated by the references. [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] For example, tacrine can target muscarnic M1 receptor with an IC 50 value of 2 µM, and donepezil can target histamine receptor 3 (IC 50 = 0.35 µM ). Figure 6 shows the number of predicted targets versus that of identified targets for six approved drugs.…”

Section: Case 1 the Prediction Of Polypharmacology For Six Known Ad mentioning

confidence: 99%

Discovery of Multitarget-Directed Ligands against Alzheimer’s Disease through Systematic Prediction of Chemical–Protein Interactions

Fang

et al. 2015

J. Chem. Inf. Model.

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To determine chemical-protein interactions (CPI) is costly, time-consuming, and labor-intensive. In silico prediction of CPI can facilitate the target identification and drug discovery. Although many in silico target prediction tools have been developed, few of them could predict active molecules against multitarget for a single disease. In this investigation, naive Bayesian (NB) and recursive partitioning (RP) algorithms were applied to construct classifiers for predicting the active molecules against 25 key targets toward Alzheimer's disease (AD) using the multitarget-quantitative structure-activity relationships (mt-QSAR) method. Each molecule was initially represented with two kinds of fingerprint descriptors (ECFP6 and MACCS). One hundred classifiers were constructed, and their performance was evaluated and verified with internally 5-fold cross-validation and external test set validation. The range of the area under the receiver operating characteristic curve (ROC) for the test sets was from 0.741 to 1.0, with an average of 0.965. In addition, the important fragments for multitarget against AD given by NB classifiers were also analyzed. Finally, the validated models were employed to systematically predict the potential targets for six approved anti-AD drugs and 19 known active compounds related to AD. The prediction results were confirmed by reported bioactivity data and our in vitro experimental validation, resulting in several multitarget-directed ligands (MTDLs) against AD, including seven acetylcholinesterase (AChE) inhibitors ranging from 0.442 to 72.26 μM and four histamine receptor 3 (H3R) antagonists ranging from 0.308 to 58.6 μM. To be exciting, the best MTDL DL0410 was identified as an dual cholinesterase inhibitor with IC50 values of 0.442 μM (AChE) and 3.57 μM (BuChE) as well as a H3R antagonist with an IC50 of 0.308 μM. This investigation is the first report using mt-QASR approach to predict chemical-protein interaction for a single disease and discovering highly potent MTDLs. This protocol may be useful for in silico multitarget prediction of other diseases.

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Rational design and synthesis of highly potent anti-acetylcholinesterase activity huperzine A derivatives

Cited by 19 publications

References 41 publications

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

Examining the Interactome of Huperzine A by Magnetic Biopanning

Discovery of Multitarget-Directed Ligands against Alzheimer’s Disease through Systematic Prediction of Chemical–Protein Interactions

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