ArticleMemorias do Instituto Oswaldo Cruz2017
Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling.
Article in Memorias do Instituto Oswaldo Cruz, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 17 citations in OpenAlex.
- Proposition ofCombinatorial chemistry & high throughput screening · 2024Review
- Synthesis,Frontiers in chemistry · 2023Article
- In silico investigation of cytochrome bc1 molecular inhibition mechanism against Trypanosoma cruzi.PLoS neglected tropical diseases · 2023Article
- Targeting the cytochrome bcMolecular diversity · 2022Review
- Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites.Scientific reports · 2021Article
- Novel Solid Dispersions of Naphthoquinone Using Different Polymers for Improvement of Antichagasic Activity.Pharmaceutics · 2020Article
- Potent inhibition of tumour cell proliferation and immunoregulatory function by mitochondria-targeted atovaquone.Scientific reports · 2020Article
- Antimalarial Agents as Therapeutic Tools Against Toxoplasmosis-A Short Bridge between Two Distant Illnesses.Molecules (Basel, Switzerland) · 2020Review
- Classical QSAR and Docking Simulation of 4-Pyridone Derivatives for Their Antimalarial Activity.Molecules (Basel, Switzerland) · 2018Article
- Characterization and Trypanocidal Activity of a Novel Pyranaphthoquinone.Molecules (Basel, Switzerland) · 2017Article
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMalaria 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.
objectivesThe 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.
methodsWe 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.
findingsResults 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
conclusionsAdditional 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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