title: QSAR, docking, dynamic simulation and quantum mechanics studies to explore the recognition properties of cholinesterase binding sites.
abstract: A set of 84 known N-aryl-monosubstituted derivatives (42 amides: series 1 and 2, and 42 imides: series 3 an 4, from maleic and succinic anhydrides, respectively) that display inhibitory activity toward both acetylcholinesterase and butyrylcholinesterase (ChEs) was considered for Quantitative structure-activity relationship (QSAR) studies. These QSAR studies employed docking data from both ChEs that were previously submitted to molecular dynamics (MD) simulations. Donepezil and galanthamine stereoisomers were included to analyze their quantum mechanics properties and for validating the docking procedure. Quantum parameters such as frontier orbital energies, dipole moment, molecular volume, atomic charges, bond length and reactivity parameters were measured, as well as partition coefficients, molar refractivity and polarizability were also analyzed. In order to evaluate the obtained equations, four compounds: 1a (4-oxo-4-(phenylamino)butanoic acid), 2a ((2Z)-4-oxo-4-(phenylamino)but-2-enoic acid), 3a (2-phenylcyclopentane-1,3-dione) and 4a (2-phenylcyclopent-4-ene-1,3-dione) were employed as independent data set, using only equations with r(m(test))²>0.5. It was observed that residual values gave low value in almost all series, excepting in series 1 for compounds 3a and 4a, and in series 4 for compounds 1a, 2a and 3a, giving a low value for 4a. Consequently, equations seems to be specific according to the structure of the evaluated compound, that means, series 1 fits better for compound 1a, series 3 or 4 fits better for compounds 3a or 4a. Same behavior was observed in the butyrylcholinesterase (BChE). Therefore, obtained equations in this QSAR study could be employed to calculate the inhibition constant (Ki) value for compounds having a similar structure as N-aryl derivatives described here. The QSAR study showed that bond lengths, molecular electrostatic potential and frontier orbital energies are important in both ChE targets. Docking studies revealed that despite the multiple conformations obtained through MD simulations on both ChEs, the ligand recognition properties were conserved. In fact, the complex formed between ChEs and the best N-aryl compound reproduced the binding mode experimentally reported, where the ligand was coupled into the choline-binding site and stabilized through π-π interactions with Trp82 or Trp86 for BChE and AChE, respectively, suggesting that this compound could be an efficient inhibitor and supporting our model.
authors: Laboratorio de Modelado Molecular y Bioinformática, Sección de Estudios de Posgrado e Investigación y Departamento de Bioquímica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340 México, D.F., Mexico. Electronic address: jcorreab@ipn.mx.
authors: J
authors: J
authors: Correa-Basurto
authors: Laboratorio de Modelado Molecular y Bioinformática, Sección de Estudios de Posgrado e Investigación y Departamento de Bioquímica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340 México, D.F., Mexico.
authors: M
authors: M
authors: Bello
authors: Laboratorio de Modelado Molecular y Bioinformática, Sección de Estudios de Posgrado e Investigación y Departamento de Bioquímica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340 México, D.F., Mexico.
authors: M C
authors: MC
authors: Rosales-Hernández
authors: Laboratorio de Modelado Molecular y Bioinformática, Sección de Estudios de Posgrado e Investigación y Departamento de Bioquímica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340 México, D.F., Mexico.
authors: M
authors: M
authors: Hernández-Rodríguez
authors: Departamento de Ciencias Químicas, Campo 1, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Av. 1ro de Mayo s/n, Col. Santa María de las Torres, Cuautitlán Izcalli, 54740 Estado de México, Mexico.
authors: I
authors: I
authors: Nicolás-Vázquez
authors: Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana, Unidad Cuajimalpa, Pedro Antonio de los Santos 84, Col. San Miguel Chapultepec, 11850 México, D.F., Mexico.
authors: A
authors: A
authors: Rojo-Domínguez
authors: Laboratorio de Modelado Molecular y Bioinformática, Sección de Estudios de Posgrado e Investigación y Departamento de Bioquímica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340 México, D.F., Mexico.
authors: J G
authors: JG
authors: Trujillo-Ferrara
authors: Departamento de Ciencias Químicas, Campo 1, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Av. 1ro de Mayo s/n, Col. Santa María de las Torres, Cuautitlán Izcalli, 54740 Estado de México, Mexico.
authors: René
authors: R
authors: Miranda
authors: Programa de Ingeniería Molecular, Instituto Mexicano del Petróleo, Eje Central Lázaro Cárdenas 152, Col. San Bartolo Atepehuacan, 07730 México, D.F., Mexico. Electronic address: caflores@imp.mx.
authors: C A
authors: CA
authors: Flores-Sandoval
mesh_terms: D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry; D002802:Cholinesterases / Q000737:chemistry* / Q000187:drug effects; D000077265:Donepezil; D016503:Drug Delivery Systems; D005702:Galantamine / Q000737:chemistry / Q000494:pharmacology; D007189:Indans / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D007189:Indans; D010880:Piperidines; D005702:Galantamine; D000077265:Donepezil; D002091:Butyrylcholinesterase; D002802:Cholinesterases
keywords: Acetylcholinesterase; Butyrylcholinesterase; DFT; MD simulation; QSAR