title: Structure-based de novo design, molecular docking and molecular dynamics of primaquine analogues acting as quinone reductase II inhibitors.
abstract: Primaquine is a traditional antimalarial drug with low parasitic resistance and generally good acceptance at higher doses, which has been used for over 60 years in malaria treatment. However, several limitations related to its hematotoxicity have been reported. It is believed that this toxicity comes from the hydroxylation of the C-5 and C-6 positions of its 8-aminoquinoline ring before binding to the molecular target: the quinone reductase II (NQO2) human protein. In this study we propose primaquine derivatives, with substitution at position C-6 of the 8-aminoquinoline ring, planned to have better binding to NQO2, compared to primaquine, but with a reduced toxicity related to the C-5 position being possible to be oxidized. On this sense the proposed analogues were suggested in order to reduce or inhibit hydroxylation and further oxidation to hemotoxic metabolites. Five C-6 substituted primaquine analogues were selected by de novo design and further submitted to docking and molecular dynamics simulations. Our results suggest that all analogues bind better to NQO2 than primaquine and may become better antimalarials. However, the analogues 3 and 4 are predicted to have a better activity/toxicity balance.
authors.affiliation: Departamento de Química, Pontifícia Universidade Católica do Rio de Janeiro, RJ 22453-900, Brazil.
authors.forename: Erika
authors.initials: E
authors.lastname: Murce
authors.affiliation: Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense (LMCBD), Military Institute of Engineering, 22290-270 Rio de Janeiro, RJ, Brazil.
authors.forename: Teobaldo Ricardo
authors.initials: TR
authors.lastname: Cuya-Guizado
authors.affiliation: Departamento de Química, Pontifícia Universidade Católica do Rio de Janeiro, RJ 22453-900, Brazil.
authors.forename: Helmut Isaac
authors.initials: HI
authors.lastname: Padilla-Chavarria
authors.affiliation: Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense (LMCBD), Military Institute of Engineering, 22290-270 Rio de Janeiro, RJ, Brazil; Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Králové, Hradec Králové, Czech Republic.
authors.forename: Tanos Celmar Costa
authors.initials: TCC
authors.lastname: França
authors.affiliation: Departamento de Química, Pontifícia Universidade Católica do Rio de Janeiro, RJ 22453-900, Brazil. Electronic address: a_pimentel@puc-rio.br.
authors.forename: Andre Silva
authors.initials: AS
authors.lastname: Pimentel
mesh_terms: D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011319:Primaquine / Q000031:analogs & derivatives* / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011808:Quinone Reductases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases; D011319:Primaquine
keywords: Malaria; Primaquine; Quinone reductase II; Toxicity; de novo design