Paulo Sa Bueno1, Franciele Av Rodrigues-Vendramini2, Marina Toplak3, Peter Macheroux3, Érika S Kioshima2, Flavio Av Seixas1. 1. Department of Technology, Universidade Estadual de Maringá, Av. Ângelo Moreira da Fonseca, 1800, 87506-370 Umuarama, PR, Brazil. 2. Department of Clinical Analysis & Biomedicine, Universidade Estadual de Maringá, Av. Colombo 5790, 87020-900 Maringá, PR, Brazil. 3. Institute of Biochemistry, Graz University of Technology, Petersgasse 12/2, 8010, Graz, Austria.
Abstract
Aim: A structural model of chorismate synthase (CS) from the pathogenic fungus Candida albicans was used for virtual screening simulations. Methods: Docking, molecular dynamics, cell growth inhibition and protein binding assays were used for search and validation. Results: Two molecules termed CS8 and CaCS02 were identified. Further studies of the minimal inhibitory concentration demonstrated fungicidal activity against Paracoccidioides brasiliensis with a minimal inhibitory concentration and minimal fungicidal concentration of 512 and 32 μg·ml-1 for CS8 and CaCS02, respectively. In addition, CaCS02 showed a strong synergistic effect in combination with amphotericin B without cytotoxic effects. In vitro studies using recombinant CS from P. brasiliensis showed IC50 of 29 μM for CaCS02 supporting our interpretation that inhibition of CS causes the observed fungicidal activity.
Aim: A structural model of chorismate synthase (CS) from the pathogenic fungus Candida albicans was used for virtual screening simulations. Methods: Docking, molecular dynamics, cell growth inhibition and protein binding assays were used for search and validation. Results: Two molecules termed CS8 and CaCS02 were identified. Further studies of the minimal inhibitory concentration demonstrated fungicidal activity against Paracoccidioides brasiliensis with a minimal inhibitory concentration and minimal fungicidal concentration of 512 and 32 μg·ml-1 for CS8 and CaCS02, respectively. In addition, CaCS02 showed a strong synergistic effect in combination with amphotericin B without cytotoxic effects. In vitro studies using recombinant CS from P. brasiliensis showed IC50 of 29 μM for CaCS02 supporting our interpretation that inhibition of CS causes the observed fungicidal activity.