title: Structural basis of femtomolar inhibitors for acetylcholinesterase subtype selectivity: insights from computational simulations.
abstract: Acetylcholinesterase (AChE) is a key enzyme of the cholinergic nervous system. More than one gene encodes the synaptic AChE target. As the most potent known AChE inhibitor, the syn1-TZ2PA6 isomer was recently shown to have higher affinity as a reversible organic inhibitor of acetylcholinesterase1 (AChE1) than the anti1-TZ2PA6 isomer. Opposite selectivity has been shown for acetylcholinesterase2 (AChE2). In an attempt to understand the selectivity of the syn1-TZ2PA6 and anti1-TZ2PA6 isomers for AChE1 and AChE2, six molecular dynamics (MD) simulations were carried out with mouse AChE (mAChE, type of AChE1), Torpedo californica AChE (TcAChE, type of AChE1), and Drosophila melanogaster AChE (DmAChE, type of AChE2) bound with syn1-TZ2PA6 and anti1-TZ2PA6 isomers. Within the structure of the inhibitor, the 3,8-diamino-6-phenylphenanthridinium subunit and 9-amino-1,2,3,4-tetrahydroacridine subunit, via π-π interactions, made more favorable contributions to syn1-TZ2PA6 or anti1-TZ2PA6 isomer binding in the mAChE/TcAChE enzyme than the 1,2,3-triazole subunit. Compared to AChE1, the triazole subunit had increased binding energy with AChE2 due to a greater negative charge in the active site. The binding free energy calculated using the MM/PBSA method suggests that selectivity between AChE1 and AChE2 is mainly attributed to decreased binding affinity for the inhibitor.
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology, College of Chemistry, Ministry of Education, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Zhu
authors.forename: Ning-Xi
authors.initials: NX
authors.lastname: Yu
authors.forename: Ge-Fei
authors.initials: GF
authors.lastname: Hao
authors.forename: Wen-Chao
authors.initials: WC
authors.lastname: Yang
authors.forename: Guang-Fu
authors.initials: GF
authors.lastname: Yang
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000166:Acridines / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000737:chemistry*; D004331:Drosophila melanogaster / Q000737:chemistry / Q000201:enzymology; D007527:Isoenzymes / Q000737:chemistry; D051379:Mice; D056004:Molecular Dynamics Simulation; D010617:Phenanthridines / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry*; D013816:Thermodynamics; D014101:Torpedo / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry
chemical_list: D000166:Acridines; D002800:Cholinesterase Inhibitors; D007527:Isoenzymes; D010617:Phenanthridines; D014230:Triazoles; D013619:Tacrine; D000110:Acetylcholinesterase