Journal ArticleDOI
Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer's drugs targeting acetyl- and butyryl-cholinesterase.
Florian Nachon,Eugénie Carletti,Cyril Ronco,Marie Trovaslet,Yvain Nicolet,Ludovic Jean,Pierre-Yves Renard +6 more
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TLDR
Huprine W in hAChE and tacrine in hBChE reside in strikingly similar positions highlighting the conservation of key interactions, namely, π-π/cation-π interactions with Trp86 (Trp82), and hydrogen bonding with the main chain carbonyl of the catalytic histidine residue.Abstract:
The multifunctional nature of Alzheimer's disease calls for MTDLs (multitarget-directed ligands) to act on different components of the pathology, like the cholinergic dysfunction and amyloid aggregation. Such MTDLs are usually on the basis of cholinesterase inhibitors (e.g. tacrine or huprine) coupled with another active molecule aimed at a different target. To aid in the design of these MTDLs, we report the crystal structures of hAChE (human acetylcholinesterase) in complex with FAS-2 (fasciculin 2) and a hydroxylated derivative of huprine (huprine W), and of hBChE (human butyrylcholinesterase) in complex with tacrine. Huprine W in hAChE and tacrine in hBChE reside in strikingly similar positions highlighting the conservation of key interactions, namely, π-π/cation-π interactions with Trp86 (Trp82), and hydrogen bonding with the main chain carbonyl of the catalytic histidine residue. Huprine W forms additional interactions with hAChE, which explains its superior affinity: the isoquinoline moiety is associated with a group of aromatic residues (Tyr337, Phe338 and Phe295 not present in hBChE) in addition to Trp86; the hydroxyl group is hydrogen bonded to both the catalytic serine residue and residues in the oxyanion hole; and the chlorine substituent is nested in a hydrophobic pocket interacting strongly with Trp439. There is no pocket in hBChE that is able to accommodate the chlorine substituent.read more
Citations
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Journal ArticleDOI
Structures of Human Acetylcholinesterase Bound to Dihydrotanshinone I and Territrem B Show Peripheral Site Flexibility
TL;DR: Structures of recombinant human acetylcholinesterase in complex with the natural product inhibitors dihydrotanshinone I and territrem B reveal diHydrotanone I binding that is specific to only the peripheral site and territ Rem B binding that spans both sites and distorts the protein backbone in the peripheral sites.
Journal ArticleDOI
Comparison of the Binding of Reversible Inhibitors to Human Butyrylcholinesterase and Acetylcholinesterase: A Crystallographic, Kinetic and Calorimetric Study.
Terrone L. Rosenberry,Xavier Brazzolotto,Ian R. Macdonald,Marielle Wandhammer,Marie Trovaslet-Leroy,Sultan Darvesh,Florian Nachon +6 more
TL;DR: Crystal structures of human BChE in complex with five reversible ligands, namely, decamethonium, thioflavin T, propidium, huprine, and ethopropazine are solved and this new information allows us to define the binding mode of various ligand families and will be of importance in designing specific reversible liganded of AChE that behave as inhibitors or reactivators.
Journal ArticleDOI
Functional constituents of wild and cultivated Goji (L. barbarum L.) leaves: phytochemical characterization, biological profile, and computational studies
Andrei Mocan,Gokhan Zengin,Mario J. Simirgiotis,Michaela Schafberg,Adriano Mollica,Dan Cristian Vodnar,Gianina Crişan,Sascha Rohn +7 more
TL;DR: Overall, Goji leaves are a rich source of bioactive compounds with functional properties that need further risk/benefit evaluation when used in foods or health-promoting formulations.
Journal ArticleDOI
Multitarget Drug Design Strategy: Quinone–Tacrine Hybrids Designed To Block Amyloid-β Aggregation and To Exert Anticholinesterase and Antioxidant Effects
Eugenie Nepovimova,Elisa Uliassi,Jan Korabecny,Luis Emiliano Peña-Altamira,Sarah Samez,Sarah Samez,Alessandro Pesaresi,Gregory E. Garcia,Manuela Bartolini,Vincenza Andrisano,Christian Bergamini,Romana Fato,Doriano Lamba,Marinella Roberti,Kamil Kuca,Barbara Monti,Maria Laura Bolognesi +16 more
TL;DR: When ex vivo results were combined with in vitro studies, these two compounds emerged to be promising multitarget lead candidates worthy of further pursuit, and crossed the blood-brain barrier, as demonstrated in ex vivo experiments with rats.
Journal ArticleDOI
Discovery and structure-activity relationships of a highly selective butyrylcholinesterase inhibitor by structure-based virtual screening
Satish N. Dighe,Girdhar Singh Deora,Eugenio de la Mora,Florian Nachon,Stephen Chan,Marie-Odile Parat,Xavier Brazzolotto,Benjamin P. Ross +7 more
TL;DR: The X-ray crystal structure of huBuChE in complex with 16 revealed the atomic-level interactions and offers opportunities for further development of the series.
References
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Multi-Target-Directed Ligands To Combat Neurodegenerative Diseases
Andrea Cavalli,Maria Laura Bolognesi,Anna Minarini,Michela Rosini,Vincenzo Tumiatti,Maurizio Recanatini,Carlo Melchiorre +6 more
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