Binding of huperzine A and galanthamine to acetylcholinesterase, based on ONIOM method

Kitisripanya, Nareerat; Saparpakorn, Pachareenart; Wolschann, Peter; Hannongbua, Supa

doi:10.1016/j.nano.2010.08.004

Cited by 32 publications

(28 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4 ) isolated from the plant Galanthus woronowii being applied for the treatment of mild to moderate AD. It is a selective, competitive, rapidly-reversible AChE inhibitor that interacts with the anionic subsite, as well as with the aromatic gorge [47-49]. Besides, the drug is an allosteric ligand at nicotinic cholinergic receptors inducing their modulation.…”

Section: Acetylcholinesterase Inhibitorsmentioning

confidence: 99%

“…4 ) is originated from the firmoss Huperzia serrata , and can be synthesized as well. The target of this AChE inhibitor is the peripheral anionic site, which makes the AD drug able to affect the symptoms as well as the cause of the disorder [55, 49] (see about donepezil above). The drug is a more potent AChE inhibitor than tacrine, galantamine and rivastigmine, while donepezil exhibits higher anti-AChE activity.…”

Section: Acetylcholinesterase Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

et al. 2013

View full text Add to dashboard Cite

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.

show abstract

Section: Acetylcholinesterase Inhibitorsmentioning

confidence: 99%

Section: Acetylcholinesterase Inhibitorsmentioning

confidence: 99%

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

et al. 2013

View full text Add to dashboard Cite

show abstract

“…QM/molecular mechanics (MM) hybrid approaches provide a possible solution to this type of problem. Some researchers have reported the application of QM/MM methods, such as ONIOM (our own n‐layered integrated molecular orbital and molecular mechanics, in predicting drug‐binding mode, residue mutation analysis, and protein‐ligand binding affinity . The applicability of ONIOM is, however, always limited by the size of its quantum region, as the atoms involved in the short‐range interactions between the drug molecule and the nearby protein residues can often add up to hundreds of atoms, which makes the necessary QM region still too large for economic scoring.…”

Section: Introductionmentioning

confidence: 99%

Nonfitting protein–ligand interaction scoring function based on first‐principles theoretical chemistry methods: Development and application on kinase inhibitors

et al. 2013

View full text Add to dashboard Cite

Targeted therapy is currently a hot topic in the fields of cancer research and drug design. An important requirement for this approach is the development of potent and selective inhibitors for the identified target protein. However, current ways to estimate inhibitor efficacy rely on empirical protein-ligand interaction scoring functions which, suffering from their heavy parameterizations, often lead to a low accuracy. In this work, we develop a nonfitting scoring function, which consists of three terms: (1) gas-phase protein-ligand binding enthalpy obtained by the eXtended ONIOM hybrid method based on an integration of density functional theory (DFT) methods (XYG3 and ωB97X-D) and the semiempirical PM6 method, (2) solvation free energy based on DFT-SMD solvation model, and (3) entropy effect estimated by using DFT frequency analysis. The new scoring function is tested on a cyclin-dependent kinase 2 (CDK2) inhibitor database including 76 CDK2 protein inhibitors and a p21-activated kinase 1 (PAK1) inhibitor database including 20 organometallic PAK1 protein inhibitors. From the results, good correlations are found between the calculated scores and the experimental inhibitor efficacies with the square of correlation coefficient R(2) of 0.76-0.88. This suggests a good predictive power of this scoring function. To the best of our knowledge, this is the first high level theory-based nonfitting scoring function with such a good level of performance. This scoring function is recommended to be used in the final screening of lead structure derivatives.

show abstract

“…As with ACh, defined interaction with both inhibitors occur within the choline/cationic-π region to optimally orientate the inhibitors to support approach and interaction with the catalytic Ser. By contrast, the natural product galantamine (Clog P value 1.02) is considered to chiefly bind within the choline/cationic-π site and with preference for AChE (Table 6a) [156]. The benzylpiperidine-based agent donepezil (cLog P value 4.6) binds within a different region still [157], the peripheral anionic site (PAS) that resides at the enterance of the gorge, and the compound extends more deeply into the mid cationic-π site.…”

Section: Introductionmentioning

confidence: 99%

New Pharmacological Approaches to the Cholinergic System: An Overview on Muscarinic Receptor Ligands and Cholinesterase Inhibitors

Greig¹,

Reale²,

Tata

2013

RPCN

View full text Add to dashboard Cite

The cholinergic system is expressed in neuronal and in non-neuronal tissues. Acetylcholine (ACh), synthesized in and out of the nervous system can locally contribute to modulation of various cell functions (e.g. survival, proliferation). Considering that the cholinergic system and its functions are impaired in a number of disorders, the identification of new pharmacological approaches to regulate cholinergic system components appears of great relevance. The present review focuses on recent pharmacological drugs able to modulate the activity of cholinergic receptors and thereby, cholinergic function, with an emphasis on the muscarinic receptor subtype, and additionally covers the cholinesterases, the main enzymes involved in ACh hydrolysis. The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells has been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. The possible involvement of ACh in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer’ and Sjogren’s diseases). The present review focuses on the potential implications of muscarinic receptors in different pathologies, including tumors. Moreover, the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice. The involvement of muscarinic receptors in nociception also is over-viewed. In fact, muscarinic agonists such as vedaclidine, CMI-936 and CMI-1145 have been demonstrated to have analgesic effects in animal models comparable or more pronounced to those produced by morphine or opiates. Likewise, the crucial role of cholinesterases (acetylcholinesterase and butirylcholinesterase) in neural transmission is discussed, as large number of drugs inhibiting cholinesterase activity have become of increasing relevance particularly for the treatment of neurodegenerative disorders. Herein we summarize the current knowledge of the cholinesterase inhibitors with particular attention to recent patents for Alzheimer’s disease drugs.

show abstract

Binding of huperzine A and galanthamine to acetylcholinesterase, based on ONIOM method

Cited by 32 publications

References 24 publications

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

Nonfitting protein–ligand interaction scoring function based on first‐principles theoretical chemistry methods: Development and application on kinase inhibitors

New Pharmacological Approaches to the Cholinergic System: An Overview on Muscarinic Receptor Ligands and Cholinesterase Inhibitors

Contact Info

Product

Resources

About