title: Alkaloids from psychotria target sirtuins: in silico and in vitro interaction studies.
abstract: Epigenetic enzymes such as histone deacetylases play a crucial role in the development of ageing-related diseases. Among the 18 histone deacetylase isoforms found in humans, class III histone deacetylases, also known as sirtuins, seem to be promising targets for treating neurodegenerative conditions. Recently, Psychotria alkaloids, mainly monoterpene indoles, have been reported for their inhibitory properties against central nervous system cholinesterase and monoamine oxidase proteins. Given the multifunctional profile of these alkaloids in the central nervous system, and the fact that the indole scaffold has been previously associated with sirtuin inhibition, we hypothesized that these indole derivatives could also interact with sirtuins. In the present study, alkaloids previously isolated from Psychotria spp. were evaluated for their potential interaction with human sirtuin 1 and sirtuin 2 by molecular docking and molecular dynamics simulation approaches. The in silico results allowed for the selection of five potentially active compounds, namely, prunifoleine, 14-oxoprunifoleine, E-vallesiachotamine, Z-vallesiachotamine, and vallesiachotamine lactone. The sirtuin inhibition of these compounds was confirmed in vitro in a dose-response manner, with preliminary information on their pharmacokinetics properties.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Lionel
authors.initials: L
authors.lastname: Sacconnay
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Lucie
authors.initials: L
authors.lastname: Ryckewaert
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Carolina
authors.initials: C
authors.lastname: Dos Santos Passos
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Guerra
authors.affiliation: Laboratório de Bioatividade Molecular, Instituto de Química, Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil.
authors.forename: Lucilia
authors.initials: L
authors.lastname: Kato
authors.affiliation: Laboratório de Bioatividade Molecular, Instituto de Química, Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil.
authors.forename: Cecilia Maria
authors.initials: CM
authors.lastname: Alves de Oliveira
authors.affiliation: Laboratório Farmacognosia, Departamento de Produção de Matéria-Prima, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Amélia
authors.initials: A
authors.lastname: Henriques
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Simões-Pires
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nurisso
mesh_terms: D000470:Alkaloids / Q000302:isolation & purification* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D032069:Psychotria / Q000737:chemistry*; D037761:Sirtuins / Q000187:drug effects*
chemical_list: D000470:Alkaloids; D037761:Sirtuins