Novel anti-Plasmodial hits identified by virtual screening of the ZINC database
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 hem...
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| Format: | Article |
| Language: | English |
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Springer
2022
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| Online Access: | https://doi.org/10.1007/s10822-013-9685-z http://hdl.handle.net/11408/4921 |
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| author | Mugumbate, Grace Newton, Ana S. Rosenthal, Philip J. Gut, Jiri Moreira, Rui Chibale, Kelly Guedes, Rita C. |
| author_facet | Mugumbate, Grace Newton, Ana S. Rosenthal, Philip J. Gut, Jiri Moreira, Rui Chibale, Kelly Guedes, Rita C. |
| author_sort | Mugumbate, Grace |
| collection | DSpace |
| description | 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. |
| format | Article |
| id | ir-11408-4921 |
| institution | My University |
| language | English |
| publishDate | 2022 |
| publisher | Springer |
| record_format | dspace |
| spelling | ir-11408-49212022-06-28T12:29:47Z Novel anti-Plasmodial hits identified by virtual screening of the ZINC database Mugumbate, Grace Newton, Ana S. Rosenthal, Philip J. Gut, Jiri Moreira, Rui Chibale, Kelly Guedes, Rita C. Malaria Antimalarials Falcipain inhibitors Virtual screening 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. 2022-06-28T12:29:47Z 2022-06-28T12:29:47Z 2013 Article 1573-4951 0920-654X https://doi.org/10.1007/s10822-013-9685-z http://hdl.handle.net/11408/4921 en Journal of Computer-Aided Molecular Design;Volume 27, pages 859–871 open Springer |
| spellingShingle | Malaria Antimalarials Falcipain inhibitors Virtual screening Mugumbate, Grace Newton, Ana S. Rosenthal, Philip J. Gut, Jiri Moreira, Rui Chibale, Kelly Guedes, Rita C. Novel anti-Plasmodial hits identified by virtual screening of the ZINC database |
| title | Novel anti-Plasmodial hits identified by virtual screening of the ZINC database |
| title_full | Novel anti-Plasmodial hits identified by virtual screening of the ZINC database |
| title_fullStr | Novel anti-Plasmodial hits identified by virtual screening of the ZINC database |
| title_full_unstemmed | Novel anti-Plasmodial hits identified by virtual screening of the ZINC database |
| title_short | Novel anti-Plasmodial hits identified by virtual screening of the ZINC database |
| title_sort | novel anti-plasmodial hits identified by virtual screening of the zinc database |
| topic | Malaria Antimalarials Falcipain inhibitors Virtual screening |
| url | https://doi.org/10.1007/s10822-013-9685-z http://hdl.handle.net/11408/4921 |
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