Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling.
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.


OBJECTIVE
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.


RESULTS
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.


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.
Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Laboratório de Modelagem Molecular e QSAR, Rio de Janeiro, RJ, Brasil.
Ana Carolina Rennó
AC
Sodero
Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Laboratório de Modelagem Molecular e QSAR, Rio de Janeiro, RJ, Brasil.
Bárbara
B
Abrahim-Vieira
Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Laboratório de Modelagem e Dinâmica Molecular, Rio de Janeiro, RJ, Brasil.|Instituto Nacional de Metrologia Qualidade e Tecnologia, Diretoria de Metrologia Aplicada às Ciências da Vida, Programa de Biotecnologia, Duque de Caxias, RJ, Brasil.
Pedro Henrique Monteiro
PH
Torres
Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Laboratório de Modelagem e Dinâmica Molecular, Rio de Janeiro, RJ, Brasil.
Pedro Geraldo
PG
Pascutti
Universidade de São Paulo, Departamento de Fisiologia, São Paulo, SP, Brasil.
Célia Rs
CR
Garcia
Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, Niterói, RJ, Brasil.
Vitor Francisco
VF
Ferreira
Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, Niterói, RJ, Brasil.
David Rodrigues da
DR
Rocha
Universidade Federal do Rio de Janeiro, Instituto de Química, Laboratório de Síntese Orgânica e Prospecção Biológica, Rio de Janeiro, RJ, Brasil.
Sabrina Baptista
SB
Ferreira
Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Bioquímica Experimental e Computacional de Fármacos, Rio de Janeiro, RJ, Brasil.
Floriano Paes
FP
Silva
D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D014450:Electron Transport Complex III / Q000737:chemistry*; D009285:Naphthoquinones / Q000737:chemistry* / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D020539:Sequence Analysis, Protein
D000962:Antimalarials; D009285:Naphthoquinones; D014450:Electron Transport Complex III; C005090:lawsone