In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen

@article{citeulike:2931223, abstract = {The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of {approx}1.7 million compounds, we identified a diverse collection of {approx}6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 {micro}M). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities. 10.1073/pnas.0802982105}, author = {Plouffe, David and Brinker, Achim and Mcnamara, Case and Henson, Kerstin and Kato, Nobutaka and Kuhen, Kelli and Nagle, Advait and Adrian, Francisco and Matzen, Jason T. and Anderson, Paul and Nam, Tae-Gyu and Gray, Nathanael S. and Chatterjee, Arnab and Janes, Jeff and Yan, Frank S. and Trager, Richard and Caldwell, Jeremy S. and Schultz, Peter G. and Zhou, Yingyao and Winzeler, Elizabeth A. }, citeulike-article-id = {2931223}, doi = {http://dx.doi.org/10.1073/pnas.0802982105}, journal = {Proceedings of the National Academy of Sciences}, keywords = {bioinformatics, malaria, network, pathway}, month = {June}, pages = {0802982105+}, posted-at = {2008-06-26 15:47:13}, priority = {2}, title = {In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen}, url = {http://dx.doi.org/10.1073/pnas.0802982105}, year = {2008} }

TY - JOUR ID - citeulike:2931223 L3 - citeulike-article-id:2931223 N2 - The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of {approx}1.7 million compounds, we identified a diverse collection of {approx}6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 {micro}M). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities. 10.1073/pnas.0802982105 JF - Proceedings of the National Academy of Sciences TI - In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen SP - 0802982105 KW - bioinformatics KW - malaria KW - network KW - pathway AU - Plouffe, David AU - Brinker, Achim AU - Mcnamara, Case AU - Henson, Kerstin AU - Kato, Nobutaka AU - Kuhen, Kelli AU - Nagle, Advait AU - Adrian, Francisco AU - Matzen, Jason AU - Anderson, Paul AU - Nam, Tae-Gyu AU - Gray, Nathanael AU - Chatterjee, Arnab AU - Janes, Jeff AU - Yan, Frank AU - Trager, Richard AU - Caldwell, Jeremy AU - Schultz, Peter AU - Zhou, Yingyao AU - Winzeler, Elizabeth PY - 2008/06/25/ UR - http://dx.doi.org/10.1073/pnas.0802982105 ER -