期刊
MEMORIAS DO INSTITUTO OSWALDO CRUZ
卷 112, 期 4, 页码 299-308出版社
FUNDACO OSWALDO CRUZ
DOI: 10.1590/0074-02760160417
关键词
atovaquone; Plasmodium falciparum; molecular docking; surflex-dock; AutoDock4.2
资金
- CNPq
- CAPES
- FAPERJ
- FAPESP [2011/51295-5]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [11/51295-5] Funding Source: FAPESP
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 bc(1) complex (Pfbc(1)) 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.
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