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Novel anti-Plasmodial hits identified by virtual screening of the ZINC database |
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| Authors: | Grace Mugumbate Ana S. Newton Philip J. Rosenthal Jiri Gut Rui Moreira Kelly Chibale Rita C. Guedes |
| Affiliation: | 1. Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa 2. Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-019, Lisbon, Portugal 3. Department of Medicine, San Francisco General Hospital, University of California, San Francisco, Box 0811, San Francisco, CA, 94143, USA 4. Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701, South Africa |
| Abstract: | Increased resistance of Plasmodium falciparum to most available drugs challenges the control of malaria. Studies with protease inhibitors have suggested important roles for the falcipain family of cysteine proteases. These enzymes act in concert with other proteases to hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. In order to find potential new antimalarial drugs, we screened in silico the ZINC database using two different protocols involving structure- and ligand-based methodologies. Our search identified 19 novel low micromolar inhibitors of cultured chloroquine resistant P. falciparum. The most active compound presented an IC50 value of 0.5 μM against cultured parasites and it also inhibited the cysteine protease falcipain-2 (IC50 = 25.5 μM). These results identify novel classes of antimalarials that are structurally different from those currently in use and which can be further derivatized to deliver leads suitable for optimisation. |
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