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

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 Q_o 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 Q_o 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.

atovaquone; Plasmodium falciparum; molecular docking; surflex-dock; AutoDock4.2