Exploring the Molecular Basis of Q o bc 1 Complex Inhibitors Activity to Find Novel Antimalarials Hits

Cytochrome bc 1 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 bc 1 complex (PDB code: 3CX5) using several reported inhibitors with experimentally determined IC 50 values against the Plasmodium falciparum bc 1 complex. We produced a molecular docking model that correlated the calculated binding free energy with the experimental inhibitory activity of each compound. This Q o 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 bc 1 complex structure as a model for the discovery of new antimalarial hits.