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

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. The aim of this work was to perform molecular modelling studi...

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Published in:Memórias do Instituto Oswaldo Cruz 2017-04, Vol.112 (4), p.299-308
Main Authors: Sodero, Ana Carolina Rennó, Abrahim-Vieira, Bárbara, Torres, Pedro Henrique Monteiro, Pascutti, Pedro Geraldo, Garcia, Célia Rs, Ferreira, Vitor Francisco, Rocha, David Rodrigues da, Ferreira, Sabrina Baptista, Silva, Jr, Floriano Paes
Format: Article
Language:English
Subjects:
Antimalarials - chemistry
Antimalarials - pharmacology
atovaquone
AutoDock4.2
Electron Transport Complex III - chemistry
molecular docking
Naphthoquinones - chemistry
Naphthoquinones - pharmacology
PARASITOLOGY
Plasmodium falciparum
Plasmodium falciparum - drug effects
Sequence Analysis, Protein
surflex-dock
TROPICAL MEDICINE
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Summary: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. 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. 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 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. 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.
ISSN:0074-0276
1678-8060
1678-8060
0074-0276
DOI:10.1590/0074-02760160417