Abstract
Cytochrome bc1 complex is a crucial element in the mitochondrial respiratory chain, being indispensable for the survival of several species of Plasmodia that cause malaria and, therefore, it is a promising target for antimalarial drug development. We report a molecular docking study building on the most recently obtained X-ray structure of the Saccharomyces cerevisiae bc1 complex (PDB code: 3CX5) using several reported inhibitors with experimentally determined IC50 values against the Plasmodium falciparum bc1 complex. We produced a molecular docking model that correlated the calculated binding free energy with the experimental inhibitory activity of each compound. This Qo model was used to search the drug-like database included in the MOE package for novel potential bc 1 complex inhibitors. Twenty three compounds were chosen to be tested for their antimalarial activity and four of these compounds demonstrated activity against the chloroquine-resistant W2 strain of P. falciparum. The most active compounds were also active against the atovaquone-resistant P. falciparum FCR3 strain and S. cerevisiae. Our study suggests the validity of the yeast bc1 complex structure as a model for the discovery of new antimalarial hits.
Original language | English |
---|---|
Pages (from-to) | 659-670 |
Number of pages | 12 |
Journal | Molecular Informatics |
Volume | 32 |
Issue number | 7 |
DOIs | |
Publication status | Published - Jul 2013 |
Externally published | Yes |
Keywords
- Docking
- Malaria
- P. falciparum
- Virtual screening