title: Exploring the Molecular Basis of Qo bc1 Complex Inhibitors Activity to Find Novel Antimalarials Hits.
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 bc1 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.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal phone/fax: +351217946477/+351217946470.
authors.forename: Marta P
authors.initials: MP
authors.lastname: Carrasco
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA 94143-0811, USA.
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.affiliation: Departement Chemie und Angewandte Biowissenschaften, Eidgenössische Technische Hochschule (ETH), Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland.
authors.forename: Tiago
authors.initials: T
authors.lastname: Rodrigues
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal phone/fax: +351217946477/+351217946470.
authors.forename: Maria H L
authors.initials: MH
authors.lastname: Ribeiro
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal phone/fax: +351217946477/+351217946470.
authors.forename: Francisca
authors.initials: F
authors.lastname: Lopes
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA 94143-0811, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal phone/fax: +351217946477/+351217946470.
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal phone/fax: +351217946477/+351217946470. dsantos@ff.ul.pt.|REQUIMTE, Department of Chemistry & Biochemistry, Faculty of Sciences, University of Porto, R. do Campo Alegre, 4169-007 Porto, Portugal. dsantos@ff.ul.pt.
authors.forename: Daniel J V A
authors.initials: DJ
authors.lastname: Dos Santos
keywords: Docking; Malaria; P. falciparum; Virtual screening; bc1 Complex