title: Receptor-dependent (RD) 3D-QSAR approach of a series of benzylpiperidine inhibitors of human acetylcholinesterase (HuAChE).
abstract: Acetylcholine inhibitors (AChEIs) are currently considered as potential drugs for treating Alzheimer disease. In this work, we developed a receptor-dependent 3D-QSAR (RD-3D-QSAR) models based on a series of 60 benzylpiperidine inhibitors of human acetylcholinesterase to support the design of new AChEIs. The best two models, A-F (N = 47, q(2) = 0.736, r(2) = 0.860) and C-F (N = 47, q(2) = 0.753, r(2) = =0.900) were developed and validated by a combined GA-PLS approach, available in WOLF. Residues of the aromatic gorge (Tyr341 and Trp439) and catalytic triad (His447) are related to both equations showing the consistency of these models with the SAR. Based on those models we have proposed four new benzylpiperidine derivatives and predicted the pIC(50) for each molecule. The good predicted potency of benzylpiperidine derivative, IIa, indicates that it is a potential candidate as a new HuAChE inhibitor.
authors.affiliation: Universidade Federal do Rio de Janeiro (UFRJ), Instituto de Química (IQ), Programa de Pós-Graduação em Química (PPGQu), Laboratório de Modelagem Molecular (LabMMol), Rio de Janeiro, RJ, Brazil. jocleymol@yahoo.com.br
authors.forename: Jocley Queiroz
authors.initials: JQ
authors.lastname: Araújo
authors.forename: Monique Araújo
authors.initials: MA
authors.lastname: de Brito
authors.forename: Lucas Villas Bôas
authors.initials: LV
authors.lastname: Hoelz
authors.forename: Ricardo Bicca
authors.initials: RB
authors.lastname: de Alencastro
authors.forename: Helena Carla
authors.initials: HC
authors.lastname: Castro
authors.forename: Carlos Rangel
authors.initials: CR
authors.lastname: Rodrigues
authors.forename: Magaly Girão
authors.initials: MG
authors.lastname: Albuquerque
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D010880:Piperidines; C032727:piperidine; D000110:Acetylcholinesterase