MEM INST OSWALDO CRUZ, RIO DE JANEIRO, 112(4) April 2017
PAGES: 299-308 DOI: 10.1590/0074-02760160417 Full paper
Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling

Ana Carolina Rennó Sodero1, Bárbara Abrahim-Vieira1, Pedro Henrique Monteiro Torres2,3, Pedro Geraldo Pascutti2, Célia RS Garcia4, Vitor Francisco Ferreira5, David Rodrigues da Rocha5, Sabrina Baptista Ferreira6, Floriano Paes Silva-Jr7,+

1Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Laboratório de Modelagem Molecular e QSAR, Rio de Janeiro, RJ, Brasil
2Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Laboratório de Modelagem e Dinâmica Molecular, Rio de Janeiro, RJ, Brasil
3Instituto Nacional de Metrologia Qualidade e Tecnologia, Diretoria de Metrologia Aplicada às Ciências da Vida, Programa de Biotecnologia, Duque de Caxias, RJ, Brasil
4Universidade de São Paulo, Departamento de Fisiologia, São Paulo, SP, Brasil
5Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, Niterói, RJ, Brasil
6Universidade Federal do Rio de Janeiro, Instituto de Química, Laboratório de Síntese Orgânica e Prospecção Biológica, Rio de Janeiro, RJ, Brasil
7Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Bioquímica Experimental e Computacional de Fármacos, Rio de Janeiro, RJ, Brasil

Abstract

BACKGROUND Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding.

OBJECTIVES The aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Qo site of P. falciparum cytochrome bc1 complex (Pfbc1) to suggest structural modifications that could improve their antimalarial activity.

METHODS We have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target.

FINDINGS Results suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Qo site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit.

MAIN CONCLUSIONS Additional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite.

Financial support: CNPq, CAPES, FAPERJ, FAPESP (2011/51295-5).
CRSG, VFF, SBF and FPS-Jr are CNPq fellows.
+ Corresponding author: This e-mail address is being protected from spambots. You need JavaScript enabled to view it.
Received 16 September 2016
Accepted 15 December 2016

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