title: Perspectives for the structure-based design of acetylcholinesterase reactivators.
abstract: Rational design of active molecules through structure-based methods has been gaining adepts during the last decades due to the wider availability of protein structures, most of them conjugated with relevant ligands. Acetylcholinesterase (AChE) is a molecular target with a considerable amount of data related to its sequence and 3-dimensional structure. In addition, there are structural insights about the mechanism of action of the natural substrate and drugs used in Alzheimer's disease, organophosphorus compounds, among others. We looked for AChE structural data useful for in silico design of potential interacting molecules. In particular, we focused on information regarding the design of ligands aimed to reactivate AChE catalytic activity. The structures of 178 AChE were annotated and categorized on different subsets according to the nature of the ligand, source organisms and experimental details. We compared sequence homology among the active site from Torpedo californica, Mus musculus and Homo sapiens with the latter two species having the closest relationship (88.9% identity). In addition, the mechanism of organophosphorus binding and the design of effective reactivators are reviewed. A curated data collection obtained with information from several sources was included for researchers working on the field. Finally, a molecular dynamics simulation with human AChE indicated that the catalytic pocket volume stabilizes around 600 Å(3), providing additional clues for drug design.
authors.affiliation: CIEMTO: Centro de Información y Estudio de Medicamentos y Tóxicos, Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad de Antioquia, Carrera 51D No. 62-42 Medellín, Colombia. Electronic address: rodrigo.ochoa@udea.edu.co.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Ochoa
authors.affiliation: CIEMTO: Centro de Información y Estudio de Medicamentos y Tóxicos, Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad de Antioquia, Carrera 51D No. 62-42 Medellín, Colombia; GRIPE: Grupo Investigador de Problemas en Enfermedades Infecciosas, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia. Electronic address: andres.rodriguez@udea.edu.co.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Rodriguez
authors.affiliation: CIEMTO: Centro de Información y Estudio de Medicamentos y Tóxicos, Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad de Antioquia, Carrera 51D No. 62-42 Medellín, Colombia; GRIPE: Grupo Investigador de Problemas en Enfermedades Infecciosas, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia. Electronic address: andres.zuluaga@udea.edu.co.
authors.forename: Andres F
authors.initials: AF
authors.lastname: Zuluaga
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D002801:Cholinesterase Reactivators / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D051379:Mice; D056004:Molecular Dynamics Simulation; D009943:Organophosphorus Compounds / Q000737:chemistry; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase; Antidotes; Computational biology; Drug discovery; Organophosphorus compounds