title: Study of the interaction of Huperzia saururus Lycopodium alkaloids with the acetylcholinesterase enzyme.
abstract: In the present study, we describe and compare the binding modes of three Lycopodium alkaloids (sauroine, 6-hydroxylycopodine and sauroxine; isolated from Huperzia saururus) and huperzine A with the enzyme acetylcholinesterase. Refinement and rescoring of the docking poses (obtained with different programs) with an all atom force field helped to improve the quality of the protein-ligand complexes. Molecular dynamics simulations were performed to investigate the complexes and the alkaloid's binding modes. The combination of the latter two methodologies indicated that binding in the active site is favored for the active compounds. On the other hand, similar binding energies in both the active and the peripheral sites were obtained for sauroine, thus explaining its experimentally determined lack of activity. MM-GBSA predicted the order of binding energies in agreement with the experimental IC50 values.
authors.affiliation: Instituto de Investigaciones en Físico Química de Córdoba (INFIQC-CONICET), Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, X5000HUA Córdoba, Argentina. mpuiatti@fcq.unc.edu.ar
authors.forename: Marcelo
authors.initials: M
authors.lastname: Puiatti
authors.forename: José Luis
authors.initials: JL
authors.lastname: Borioni
authors.forename: Mariana Guadalupe
authors.initials: MG
authors.lastname: Vallejo
authors.forename: José Luis
authors.initials: JL
authors.lastname: Cabrera
authors.forename: Alicia Mariel
authors.initials: AM
authors.lastname: Agnese
authors.forename: María Gabriela
authors.initials: MG
authors.lastname: Ortega
authors.forename: Adriana Beatríz
authors.initials: AB
authors.lastname: Pierini
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000470:Alkaloids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D032501:Huperzia / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D032502:Lycopodium / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase inhibitors; Docking; Lycopodium alkaloids; Molecular dynamics; Sauroxine