ArticleThe Biochemical journal1998
The 'aromatic patch' of three proximal residues in the human acetylcholinesterase active centre allows for versatile interaction modes with inhibitors.
Article in The Biochemical journal, 1998. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Design, Synthesis, and Evaluation of Pyrrole-Based Selective MAO-B Inhibitors with Additional AChE Inhibitory and Neuroprotective Properties Identified via Virtual Screening.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Exploring Novel Quinoline-1,3,4-Oxadiazole Derivatives for Alzheimer's Disease: Their Design, Synthesis, andCurrent medicinal chemistry · 2025Article
- Article
- Pharmacophore mapping of the crucial mediators of acetylcholinesterase and butyrylcholinesterase dual inhibition in Alzheimer's disease.Molecular diversity · 2022Article
- Improved machine learning scoring functions for identification of Electrophorus electricus's acetylcholinesterase inhibitors.Molecular diversity · 2022Article
- ABCpred: a webserver for the discovery of acetyl- and butyryl-cholinesterase inhibitors.Molecular diversity · 2022Article
- Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE.International journal of molecular sciences · 2021Article
- Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach.Scientific reports · 2021Article
- Guided Evolution of RecombinantInternational journal of molecular sciences · 2018Article
- Pharmacophore-based design and discovery of (-)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis.Journal of enzyme inhibition and medicinal chemistry · 2017Article
- Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer's Agents: Design, Synthesis and Biological Evaluation.Molecules (Basel, Switzerland) · 2017Article
- Neuroprotective Role of Novel Triazine Derivatives by Activating Wnt/β Catenin Signaling Pathway in Rodent Models of Alzheimer's Disease.Molecular neurobiology · 2015Article
- A wrench in the works of human acetylcholinesterase: soman induced conformational changes revealed by molecular dynamics simulations.PloS one · 2015Article
- Acetylcholinesterase inhibitors: pharmacology and toxicology.Current neuropharmacology · 2013Article
- Article
- Immobilized butyrylcholinesterase in the characterization of new inhibitors that could ease Alzheimer's disease.Journal of chromatography. A · 2009Article
- Accommodation of physostigmine and its analogues by acetylcholinesterase is dominated by hydrophobic interactions.The Biochemical journal · 2009Article
- Functional proteomic and structural insights into molecular recognition in the nitrilase family enzymes.Biochemistry · 2008Article
- Flexibility versus "rigidity" of the functional architecture of AChE active center.Chemico-biological interactions · 2008Article
- Acetylcholinesterase in the sea urchin Lytechinus variegatus: characterization and developmental expression in larvae.Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology · 2008Article
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6 authors.
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Abstract
The role of the functional architecture of the human acetylcholinesterase (HuAChE) active centre in accommodating the non-covalent inhibitors tacrine and huperzine A, or the carbamates pyridostigmine and physostigmine, was analysed using 16 mutants of residues lining the active-centre gorge. Despite the structural diversity of the ligands, certain common properties of the complexes could be observed: (a) replacement of aromatic residues Tyr133, Tyr337 and especially Trp86, resulted in pronounced changes in stability of all the complexes examined; (b) effects due to replacements of the five other aromatic residues along the active-centre gorge, such as the acyl pocket (Phe295, Phe297) or at the peripheral anionic site (Tyr124, Trp286, Tyr341) were relatively small; (c) effects due to substitution of the carboxylic residues in the gorge (Glu202, Glu450) were moderate. These results and molecular modelling indicate that the aromatic side chains of residues Trp86, Tyr133 and Tyr337 form together a continuous 'aromatic patch' lining the wall of the active-centre gorge, allowing for the accommodation of the different ligands via multiple modes of interaction. Studies with HuAChE mutants carrying replacements at positions 86, 133 and 337 indicate that the orientations of huperzine A and tacrine in the HuAChE complexes in solution are significantly different from those observed in X-ray structures of the corresponding complexes with Torpedo californica AChE (TcAChE). These discrepancies may be explained in terms of structural differences between the complexes of HuAChE and TcAChE or, more likely, by the enhanced flexibility of the AChE active-centre gorge in solution as compared with the crystalline state.
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