Probing the Open Global Health Chemical Diversity Library for Multistage-Active Starting Points for Next-Generation Antimalarials
| Autor: | Manu Vanaerschot, David A. Fidock, Kerstin Gagaring, Karla P. Godinez-Macias, Jaeson Calla, Yevgeniya Antonova-Koch, Case W. McNamara, Madeline R. Luth, Melanie Wree, Elizabeth A. Winzeler, Sabine Ottilie, Marisa L. Martino, Korina Eribez, David Plouffe, Alan Y. Du, Matthew Abraham |
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| Rok vydání: | 2020 |
| Předmět: |
chemoinformatic analysis
0301 basic medicine whole genome sequencing (WGS) Plasmodium falciparum 030106 microbiology Drug Evaluation Preclinical malaria Computational biology Biology Article drug discovery Small Molecule Libraries Antimalarials 03 medical and health sciences medicine Global health Life Cycle Stages Drug discovery Cheminformatics multistage antimalarials medicine.disease High-Throughput Screening Assays Blood stage 030104 developmental biology Infectious Diseases Chemical diversity Malaria |
| Zdroj: | ACS Infectious Diseases |
| ISSN: | 2373-8227 |
| Popis: | Most phenotypic screens aiming to discover new antimalarial chemotypes begin with low cost, high-throughput tests against the asexual blood stage (ABS) of the malaria parasite life cycle. Compounds active against the ABS are then sequentially tested in more difficult assays that predict whether a compound has other beneficial attributes. Although applying this strategy to new chemical libraries may yield new leads, repeated iterations may lead to diminishing returns and the rediscovery of chemotypes hitting well-known targets. Here, we adopted a different strategy to find starting points, testing ∼70,000 open source small molecules from the Global Health Chemical Diversity Library for activity against the liver stage, mature sexual stage, and asexual blood stage malaria parasites in parallel. In addition, instead of using an asexual assay that measures accumulated parasite DNA in the presence of compound (SYBR green), a real time luciferase-dependent parasite viability assay was used that distinguishes slow-acting (delayed death) from fast-acting compounds. Among 382 scaffolds with the activity confirmed by dose response ( |
| Databáze: | OpenAIRE |
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