Fels G


Full name : Fels Gregor

First name : Gregor

Mail : Department of Chemistry, University of Paderborn, Warburgerstr. 100, D-33098, Paderborn

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Country : Germany

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References (10)

Title : Probing Torpedo californica acetylcholinesterase catalytic gorge with two novel bis-functional galanthamine derivatives - Bartolucci_2010_J.Med.Chem_53_745
Author(s) : Bartolucci C , Haller LA , Jordis U , Fels G , Lamba D
Ref : Journal of Medicinal Chemistry , 53 :745 , 2010
Abstract : N-Piperidinopropyl-galanthamine (2) and N-saccharinohexyl-galanthamine (3) were used to investigate interaction sites along the active site gorge of Torpedo californica actylcholinesterase (TcAChE). The crystal structure of TcAChE-2 solved at 2.3 A showed that the N-piperidinopropyl group in 2 is not stretched along the gorge but is folded over the galanthamine moiety. This result was unexpected because the three carbon alkyl chain is just long enough for the bulky piperidine group to be placed above the bottleneck (Tyr121, Phe330) midway down the gorge. The crystal structure of TcAChE-3 at 2.2 A confirmed that a dual interaction with the sites at the bottom, and at the entrance of the gorge, enhances inhibitory activity: a chain of six carbon atoms has, in this class of derivatives, the correct length for optimal interactions with the peripheral anionic site (PAS).
ESTHER : Bartolucci_2010_J.Med.Chem_53_745
PubMedSearch : Bartolucci_2010_J.Med.Chem_53_745
PubMedID: 20025280
Gene_locus related to this paper: torca-ACHE

Title : Localization by site-directed mutagenesis of a galantamine binding site on alpha7 nicotinic acetylcholine receptor extracellular domain - Ludwig_2010_J.Recept.Signal.Transduct.Res_30_469
Author(s) : Ludwig J , Hoffle-Maas A , Samochocki M , Luttmann E , Albuquerque EX , Fels G , Maelicke A
Ref : J Recept Signal Transduct Res , 30 :469 , 2010
Abstract : Galantamine is an approved drug treatment for Alzheimer's disease. Initially identified as a weak cholinesterase inhibitor, we have established that galantamine mainly acts as an 'allosterically potentiating ligand (APL)' of nicotinic acetylcholine receptors (nAChR). Meanwhile other 'positive allosteric modulators (PAM)' of nAChR channel activity have been discovered, and for one of them a binding site within the transmembrane domain has been proposed. Here we show, by performing site-directed mutagenesis studies of ectopically expressed chimeric chicken alpha7/mouse 5-hydroxytryptamine 3 receptor-channel complex, in combination with whole-cell current measurements, in the presence and absence of galantamine, that the APL binding site is different from the proposed PAM binding site. We demonstrate that residues T197, I196, and F198 of ss-strand 10 represent major elements of the galantamine binding site. Residue K123, earlier suggested as being 'close to' the APL binding site, is not part of this site but rather appears to play a role in coupling of agonist binding to channel opening and closing. Our data confirm our earlier results that the galantamine binding site is different from the ACh binding site. Both sites are in close proximity and hence may influence each other in a synergistic fashion. Other interesting areas identified in the present study are a 'hinge' region around and containing residues F122, K123, and K143 possibly being involved in relaying the signal of agonist binding to gating of the transmembrane channel, and a 'folding centre', with P119 as the dominating residue, that crucially positions the agonist binding site with respect to the hinge region.
ESTHER : Ludwig_2010_J.Recept.Signal.Transduct.Res_30_469
PubMedSearch : Ludwig_2010_J.Recept.Signal.Transduct.Res_30_469
PubMedID: 21062106

Title : Molecular docking study on the back door hypothesis for product clearance in acetylcholinesterase - Alisaraie_2006_J.Mol.Model_12_348
Author(s) : Alisaraie L , Fels G
Ref : J Mol Model , 12 :348 , 2006
Abstract : Acetylcholinesterase (AChE) is one of the fastest enzymes known, even though the active site is buried inside the protein at the end of a 20-A deep narrow gorge. Among the great variety of crystal structures of this enzyme, both in the absence and presence of various ligands and proteins, the structure of a complex of AChE with the pseudo-irreversible inhibitor Mf268 is of particular interest, as it assists in the proposal of a back door for product clearance from the active site. Binding of Mf268 to AChE results in the carbamoylation of Ser200 and liberation of an eseroline-fragment as the leaving group. The crystal structure of the AChE-Mf268 complex, however, proves that eseroline has escaped from the enzyme, despite the fact that the Ser-bound inhibitor fragment blocks the gorge entrance. The existence of alternative routes other than through the gorge for product clearance has been postulated but is still controversially discussed in the literature, as an experimental proof for such a back door is still missing. We have used Monte Carlo-based molecular docking methods in order to examine possible alternative pathways that could allow eseroline to be released from the protein after being cleaved from the substrate by Ser200. Based on our results, a short channel at the bottom of the gorge seems to be the most probable back-door site, which begins at amino acid Trp84 and ends at the enzyme surface in a cavity close to amino acid Glu445. [Figure: see text].
ESTHER : Alisaraie_2006_J.Mol.Model_12_348
PubMedSearch : Alisaraie_2006_J.Mol.Model_12_348
PubMedID: 16341717

Title : A QXP-based multistep docking procedure for accurate prediction of protein-ligand complexes - Alisaraie_2006_J.Chem.Inf.Model_46_1174
Author(s) : Alisaraie L , Haller LA , Fels G
Ref : J Chem Inf Model , 46 :1174 , 2006
Abstract : The two great challenges of the docking process are the prediction of ligand poses in a protein binding site and the scoring of the docked poses. Ligands that are composed of extended chains in their molecular structure display the most difficulties, predominantly because of the torsional flexibility. On the basis of the molecular docking program QXP-Flo+0802, we have developed a procedure particularly for ligands with a high degree of rotational freedom that allows the accurate prediction of the orientation and conformation of ligands in protein binding sites. Starting from an initial full Monte Carlo docking experiment, this was achieved by performing a series of successive multistep docking runs using a local Monte Carlo search with a restricted rotational angle, by which the conformational search space is limited. The method was established by using a highly flexible acetylcholinesterase inhibitor and has been applied to a number of challenging protein-ligand complexes known from the literature.
ESTHER : Alisaraie_2006_J.Chem.Inf.Model_46_1174
PubMedSearch : Alisaraie_2006_J.Chem.Inf.Model_46_1174
PubMedID: 16711737

Title : Buprofezin and novaluron inhibit acetylcholinesterase activity in B-biotype Bemisia tabaci. -
Author(s) : Luttmann E , Linnemann E , Fels G
Ref : Cholinergic Mechanisms, CRC Press :631 , 2004

Title : Galanthamine as bis-functional ligand for the acetylcholinesterase - Luttmann_2002_J.Mol.Model.(Online)_8_208
Author(s) : Luttmann E , Linnemann E , Fels G
Ref : J Mol Model (Online) , 8 :208 , 2002
Abstract : Acetylcholinesterase plays a key role in the development of Alzheimer's disease as this enzyme is responsible for cleavage of the neurotransmitter acetylcholine, and, according to recent investigations, also promotes aggregation of beta-amyloid peptides, which causes plaque formation in synaptic areas. We have performed a molecular modeling study to investigate bis-galanthamine derivatives connected by a methylene spacer of varying length as dual acting acetylcholinesterase ligands. Our results suggest that such ligands indeed can interact simultaneously with both biological functions of the enzyme and should therefore serve as the basis for a further development of bis-functional Alzheimer drugs.
ESTHER : Luttmann_2002_J.Mol.Model.(Online)_8_208
PubMedSearch : Luttmann_2002_J.Mol.Model.(Online)_8_208
PubMedID: 12140604

Title : Three-dimensional structure of a complex of galanthamine (Nivalin) with acetylcholinesterase from Torpedo californica: implications for the design of new anti-Alzheimer drugs - Bartolucci_2001_Proteins_42_182
Author(s) : Bartolucci C , Perola E , Pilger C , Fels G , Lamba D
Ref : Proteins , 42 :182 , 2001
Abstract : The 3D structure of a complex of the anti-Alzheimer drug galanthamine with Torpedo californica acetylcholinesterase is reported. Galanthamine, a tertiary alkaloid extracted from several species of Amarylidacae, is so far the only drug that shows a dual activity, being both an acetylcholinesterase inhibitor and an allosteric potentiator of the nicotinic response induced by acetylcholine and competitive agonists. The X-ray structure, at 2.5A resolution, shows an unexpected orientation of the ligand within the active site, as well as unusual protein-ligand interactions. The inhibitor binds at the base of the active site gorge, interacting with both the acyl-binding pocket and the principal quaternary ammonium-binding site. However, the tertiary amine group of galanthamine does not directly interact with Trp84. A docking study using the program AUTODOCK correctly predicts the orientation of galanthamine in the active site. The docked lowest-energy structure has a root mean square deviation of 0.5A with respect to the corresponding crystal structure of the complex. The observed binding mode explains the affinities of a series of structural analogs of galanthamine and provides a rational basis for structure-based drug design of synthetic derivatives with improved pharmacological properties. Proteins 2001;42:182-191.
ESTHER : Bartolucci_2001_Proteins_42_182
PubMedSearch : Bartolucci_2001_Proteins_42_182
PubMedID: 11119642
Gene_locus related to this paper: torca-ACHE

Title : Accurate prediction of the bound conformation of galanthamine in the active site of Torpedo californica acetylcholinesterase using molecular docking - Pilger_2001_J.Mol.Graph.Model_19_288
Author(s) : Pilger C , Bartolucci C , Lamba D , Tropsha A , Fels G
Ref : J Mol Graph Model , 19 :288 , 2001
Abstract : The alkaloid (-)-galanthamine is known to produce significant improvement of cognitive performances in patients with the Alzheimer's disease. Its mechanism of action involves competitive and reversible inhibition of acetylcholinesterase (AChE). Herein, we correctly predict the orientation and conformation of the galanthamine molecule in the active site of AChE from Torpedo californica (TcAChE) using a combination of rigid docking and flexible geometry optimization with a molecular mechanics force field. The quality of the predicted model is remarkable, as indicated by the value of the RMS deviation of approximately 0.5A when compared with the crystal structure of the TcAChE-galanthamine complex. A molecular model of the complex between TcAChE and a galanthamine derivative, SPH1107, with a long chain substituent on the nitrogen has been generated as well. The side chain of this ligand is predicted to extend along the enzyme active site gorge from the anionic subsite, at the bottom, to the peripheral anionic site, at the top. The docking procedure described in this paper can be applied to produce models of ligand-receptor complexes for AChE and other macromolecular targets of drug design.
ESTHER : Pilger_2001_J.Mol.Graph.Model_19_288
PubMedSearch : Pilger_2001_J.Mol.Graph.Model_19_288
PubMedID: 11449566

Title : Synthesis and properties of NBD-n-acylcholines, fluorescent analogs of acetylcholine - Meyers_1983_Eur.J.Biochem_137_399
Author(s) : Meyers HW , Jurss R , Brenner HR , Fels G , Prinz H , Watzke H , Maelicke A
Ref : European Journal of Biochemistry , 137 :399 , 1983
Abstract : We have synthesized a homologous series of fluorescent analogs of acetylcholine, N-7-(4-nitrobenzo-2-oxa-1,3-diazolyl)-omega-amino-n-alkanoic acid beta (N,N,N-trialkylammonium) ethylesters (NBD-n-acylcholines) and report here on their physiological and biochemical properties. All NBD-n-acylcholines trimethylated at the cholinergic nitrogen are agonists of acetylcholine at the frog neuromuscular junction. Their potencies in depolarizing frog muscle cells decrease with decreasing chain length. The affinities of binding to the purified receptor from Electrophorus electricus also decrease with decreasing chain length with a large drop in affinity for the derivatives n = 4 and n = 3. The rate constants of association to acetylcholine receptor and to acetylcholine esterase are of the order of 10(8) M-1 S-1 and do not vary significantly with the chain length of the NBD-n-acylcholines. In contrast, the dissociation rate constants decrease with increasing chain length. The quenching of fluorescence of NBD-n-acylcholines accompanying binding to purified receptor and esterase from E. electricus appears to be due to the formation of a hydrogen bond between the omega-amino group as donor and an unidentified acceptor group in a hydrophobic pocket of the protein. With their advantageous fluorescence properties, their simple pharmacology, and their clear structure-function relationships, these compounds are useful tools for the study of cholinergic mechanisms.
ESTHER : Meyers_1983_Eur.J.Biochem_137_399
PubMedSearch : Meyers_1983_Eur.J.Biochem_137_399
PubMedID: 6607162

Title : Agonist-activated ionic channels in acetylcholine receptor reconstituted into planar lipid bilayers - Boheim_1981_Proc.Natl.Acad.Sci.U.S.A_78_3586
Author(s) : Boheim G , Hanke W , Barrantes FJ , Eibl H , Sakmann B , Fels G , Maelicke A
Ref : Proc Natl Acad Sci U S A , 78 :3586 , 1981
Abstract : Planar lipid bilayers were formed with the mixed chain phospholipid 1-stearoyl-3-myristolglycero-2-phosphocholine. Acetylcholine receptor membrane fragments or the purified receptor protein was incorporated into these bilayers by fusing receptor-containing vesicles with the planar membranes a few degrees below the lipid phase transition temperature. Single-channel currents activated by nicotinic agonists in the reconstituted system resembled those observed in intact rat and frog muscle membrane as measured by the patch clamp technique. The observed channel characteristics did not depend on the degree of receptor purification. Thus, the receptor-enriched fragments and those depleted of nonreceptor peripheral peptides, the purified receptor monomer/dimer mixtures, and the isolated receptor monomer as defined by gel electrophoresis all shared similar electrochemical properties in the synthetic lipid bilayer. The agonist-activated ionic channel seems, therefore, to be contained within the receptor monomer.
ESTHER : Boheim_1981_Proc.Natl.Acad.Sci.U.S.A_78_3586
PubMedSearch : Boheim_1981_Proc.Natl.Acad.Sci.U.S.A_78_3586
PubMedID: 6267599