title: Revealing the Binding Process of New 3-Alkylpyridine Marine Alkaloid Analogue Antimalarials and the Heme Group: An Experimental and Theoretical Investigation.
abstract: Synthetic 3-alkylpyridine marine alkaloid (3-APA) analogues have shown good antimalarial activity against Plasmodium falciparum. However, despite their structural originality, their molecular target was unknown. Herein, we report a proposal for the antimalarial mechanism of action of 3-APA analogues through interference with the process of hemozoin (Hz) formation. The interaction between 3-APA analogues and heme groups was investigated employing an in silico approach and biophysical techniques such as ultraviolet-visible light (UV-vis) titration and electrospray ionization-mass spectrometry (ESI-MS). The in silico approach was performed based on pure ab initio electronic structure methods in order to obtain insights at the molecular level concerning the binding process of antimalarial drugs at their target site, the heme group. In silico results showed that the formation of heme:3-APA complexes at a molecular ratio of 2:1 are more stable than 1:1 complexes. These results were further confirmed by experimental techniques, such as UV-vis and high-resolution mass spectrometry (ESI-TOF), for two of the most active 3-APA analogues.
authors.affiliation: Departamento de Bioquímica e Biotecnologia, CCE, Universidade Estadual de Londrina , Londrina, PR 86057-970, Brazil.
authors.forename: Renato M
authors.initials: RM
authors.lastname: Ribeiro-Viana
authors.affiliation: Departamento de Química, CCE, Universidade Estadual de Londrina , Londrina, PR 86057-970, Brazil.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Butera
authors.affiliation: Departamento de Ciências Naturais (DCNAT), Universidade Federal de São João del-Rei , Campus Dom Bosco, São João Del Rei, MG 36301-160, Brazil.
authors.forename: Eliziane S
authors.initials: ES
authors.lastname: Santos
authors.affiliation: Departamento de Bioquímica e Biotecnologia, CCE, Universidade Estadual de Londrina , Londrina, PR 86057-970, Brazil.
authors.forename: César A
authors.initials: CA
authors.lastname: Tischer
authors.affiliation: Departamento de Química, Instituto de Ciências Exatas (ICEx), Universidade Federal de Minas Gerais (UFMG) , Av. Pres, Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil.
authors.forename: Rosemeire B
authors.initials: RB
authors.lastname: Alves
authors.affiliation: Departamento de Química, Instituto de Ciências Exatas (ICEx), Universidade Federal de Minas Gerais (UFMG) , Av. Pres, Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil.
authors.forename: Rossimiriam
authors.initials: R
authors.lastname: Pereira de Freitas
authors.affiliation: Departamento de Ciências Naturais (DCNAT), Universidade Federal de São João del-Rei , Campus Dom Bosco, São João Del Rei, MG 36301-160, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Guimarães
authors.affiliation: Núcleo de Pesquisa em Química Biológica (NQBio), Universidade Federal de São João del-Rei , Campus Centro-Oeste, Divinópolis, MG 35501-296, Brazil.
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Varotti
authors.affiliation: Núcleo de Pesquisa em Química Biológica (NQBio), Universidade Federal de São João del-Rei , Campus Centro-Oeste, Divinópolis, MG 35501-296, Brazil.
authors.forename: Gustavo H R
authors.initials: GH
authors.lastname: Viana
authors.affiliation: Departamento de Ciências Naturais (DCNAT), Universidade Federal de São João del-Rei , Campus Dom Bosco, São João Del Rei, MG 36301-160, Brazil.
authors.forename: Clebio S
authors.initials: CS
authors.lastname: Nascimento
mesh_terms: D000470:Alkaloids / Q000737:chemistry*; D000962:Antimalarials / Q000737:chemistry*; D001665:Binding Sites; D006418:Heme / Q000378:metabolism*; D008386:Marine Biology; D011725:Pyridines / Q000737:chemistry*
chemical_list: D000470:Alkaloids; D000962:Antimalarials; D011725:Pyridines; D006418:Heme