Accurate prediction of the bound conformation of galanthamine in the active site of torpedo californica acetylcholinesterase using molecular docking

Pilger, Christian; Bartolucci, Cecilia; Lamba, Doriano; Tropsha, Alexander; Fels, Gregor

doi:10.1016/s1093-3263(00)00056-5

Cited by 54 publications

(38 citation statements)

References 40 publications

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“…103 ). Beside the α-anionic site, galantamine also binds at another important part of the AChE active site including aromatic gorge 104,105 . The formulas of these compounds are shown in (Fig.…”

Section: Inhibitors Of the α-Anionic Sitementioning

confidence: 99%

Cholinesterases, a Target of Pharmacology and Toxicology

Pohanka¹

2011

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

325

219

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Background. Cholinesterases are a group of serine hydrolases that split the neurotransmitter acetylcholine (ACh) and terminate its action. Of the two types, butyrylcholinesterase and acetylcholinesterase (AChE), AChE plays the key role in ending cholinergic neurotransmission. Cholinesterase inhibitors are substances, either natural or man-made that interfere with the break-down of ACh and prolong its action. Hence their relevance to toxicology and pharmacology.Methods and Results. The present review summarizes current knowledge of the cholinesterases and their inhibition. Particular attention is paid to the toxicology and pharmacology of cholinesterase-related inhibitors such as nerve agents (e.g. sarin, soman, tabun, VX), pesticides (e.g. paraoxon, parathion, malathion, malaoxon, carbofuran), selected plants and fungal secondary metabolites (e.g. aflatoxins), drugs for Alzheimer's disease (e.g. huperzine, metrifonate, tacrine, donepezil) and Myasthenia gravis (e.g. pyridostigmine) treatment and other compounds (propidium, ethidium, decamethonium).Conclusions. The crucial role of the cholinesterases in neural transmission makes them a primary target of a large number of cholinesterase-inhibiting drugs and toxins. In pharmacology, this has relevance to the treatment of neurodegenerative disorders.

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Section: Inhibitors Of the α-Anionic Sitementioning

confidence: 99%

Cholinesterases, a Target of Pharmacology and Toxicology

Pohanka¹

2011

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

325

219

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“…For the docking analysis, the ligand was obtained by separating the same from the complex domain of pdb accession code 1VOT [1] and converted into pdb format, whereas the threedimensional structure of AChE of "Torpedo californica" was prepared by separating AChE form the complex domain of pdb accession code 1QTI [50] obtained from Brookhaven Protein Data Bank. Autodock generated 10 different conformations and their corresponding docked energies (Table S1).…”

Section: Calculationsmentioning

confidence: 99%

Conformational Flexibility and the Interaction of Huperzine A in the Active Site of Acetylcholinesterase: A Quantum Chemical and Charge Density Study

Kandasamy

Kumaradhas

2016

Preprint

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“…Unfortunately, when using a generic docking protocol, usually not all of the docked conformations end up inside the active site cavity [31]. Structural analysis of the available crystallized complexes from PDB led to the assumption that the bisbenzyl substituted TMB-4 compounds (4) interact at the bottom of the gorge with additional contacts along the gorge and the gorge entrance.…”

Section: Docking Studiesmentioning

confidence: 99%

“…The Brookhaven Protein Data Bank (PDB) [30] contains several small molecule-AChE complexes. Some of them were already used for docking experiments, including the Torpedo californica AChE (TcAChE) complex with decamethonium (1ACL), edrophonium (2ACK), tacrine (1ACJ), and huperzine A (1VOT), respectively [31,32] Owing to their size and shape a gorge-spanning binding mode for the tested compounds was assumed. Therefore, the crystal structure of co-crystallized donepezil (1EVE) was used during this study.…”

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confidence: 99%

“…Results of these studies were comparable for all three programs. Since AUTODOCK was already successfully applied for published docking studies with AChE [31,32], it was selected here.Investigation of the active site of AChE allows the identification of one peripheral anionic site (PAS) and at least five major binding sites: the oxyanion hole (OH), the esteratic site (ES), the anionic substrate binding site (AS), the active site-selective aromatic binding site (AACS), and the acyl binding site (ACS) [38,39]. Due to this wide variety of possible binding sites, docking results were expected to be highly diverse.…”

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confidence: 99%

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Synthesis, Biological Activity, and Docking Studies of New Acetylcholinesterase Inhibitors of the Bispyridinium Type

Kapková

Stiefl

Sürig

et al. 2003

Archiv der Pharmazie

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A novel series of acetylcholinesterase (AChE) inhibitors of the bispyridinium type was synthesized and the inhibitory activity against AChE and butyrylcholinesterase (BChE) measured. In essence, the substitution pattern influenced the inhibitory potency against AChE, where the most active bispyridiniumoxime (TMB-4) was bisbenzyl substituted followed by monobenzyl substituted, bismethyl substituted, and unsubstituted derivatives of TMB-4. Hence, the bisbenzyl ether of TMB-4 was further investigated. In order to obtain diverse lipophilic and electronic properties for these bisbenzyl bispyridinium derivatives (so-called DUO series), the lateral ring substitution was systematically varied. The lowest IC(50) value against AChE found thus far in the DUO series was 0.34 microM. Docking studies were carried out to elucidate the differences in biological activity. A general binding mode for nearly all compounds could be identified by these investigations. In this binding mode, the docked ligands span the narrow, deeply buried active-site gorge, interacting with Trp84 at the bottom of the gorge, Tyr334 or Phe331 halfway down the gorge, and Trp279 at the peripheral anionic site at the mouth of the gorge. For specific ligands, additional interactions were found which helped to explain their deviating activity. Based on the promising characteristics of the novel acetylcholinesterase inhibitors presented, a series of structurally related, optimized candidates will be developed.

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Accurate prediction of the bound conformation of galanthamine in the active site of torpedo californica acetylcholinesterase using molecular docking

Cited by 54 publications

References 40 publications

Cholinesterases, a Target of Pharmacology and Toxicology

Cholinesterases, a Target of Pharmacology and Toxicology

Conformational Flexibility and the Interaction of Huperzine A in the Active Site of Acetylcholinesterase: A Quantum Chemical and Charge Density Study

Synthesis, Biological Activity, and Docking Studies of New Acetylcholinesterase Inhibitors of the Bispyridinium Type

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