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Exploring the Molecular Basis of Q o bc 1 Complex Inhibitors Activity to Find Novel Antimalarials Hits
Author(s) -
Carrasco Marta P.,
Gut Jiri,
Rodrigues Tiago,
Ribeiro Maria H. L.,
Lopes Francisca,
Rosenthal Philip J.,
Moreira Rui,
dos Santos Daniel J. V. A.
Publication year - 2013
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201300024
Subject(s) - basis (linear algebra) , computer science , computational biology , chemistry , biology , mathematics , geometry
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.