An open drug discovery competition : experimental validation of predictive models in a series of novel antimalarials

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Tse, Edwin G. and Aithani, Laksh and Anderson, Mark and Cardoso-Silva, Jonathan and Cincilla, Giovanni and Conduit, Gareth J. and Galushka, Mykola and Guan, Davy and Hallyburton, Irene and Irwin, Benedict W. J. and Kirk, Kiaran and Lehane, Adele M. and Lindblom, Julia C. R. and Lui, Raymond and Matthews, Slade and McCulloch, James and Motion, Alice and Ng, Ho Leung and Öeren, Mario and Robertson, Murray N. and Spadavecchio, Vito and Tatsis, Vasileios A. and van Hoorn, Willem P. and Wade, Alexander D. and Whitehead, Thomas M. and Willis, Paul and Todd, Matthew H. (2021) An open drug discovery competition : experimental validation of predictive models in a series of novel antimalarials. Journal of Medicinal Chemistry, 64 (22). pp. 16450-16463. ISSN 0022-2623 (https://doi.org/10.1021/acs.jmedchem.1c00313)

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Abstract

The Open Source Malaria (OSM) consortium is developing compounds that kill the human malaria parasite, , by targeting ATP4, an essential ion pump on the parasite surface. The structure of ATP4 has not been determined. Here, we describe a public competition created to develop a predictive model for the identification of ATP4 inhibitors, thereby reducing project costs associated with the synthesis of inactive compounds. Competition participants could see all entries as they were submitted. In the final round, featuring private sector entrants specializing in machine learning methods, the best-performing models were used to predict novel inhibitors, of which several were synthesized and evaluated against the parasite. Half possessed biological activity, with one featuring a motif that the human chemists familiar with this series would have dismissed as "ill-advised". Since all data and participant interactions remain in the public domain, this research project "lives" and may be improved by others.

ORCID iDs

Tse, Edwin G., Aithani, Laksh, Anderson, Mark, Cardoso-Silva, Jonathan, Cincilla, Giovanni, Conduit, Gareth J., Galushka, Mykola, Guan, Davy, Hallyburton, Irene, Irwin, Benedict W. J., Kirk, Kiaran, Lehane, Adele M., Lindblom, Julia C. R., Lui, Raymond, Matthews, Slade, McCulloch, James, Motion, Alice, Ng, Ho Leung, Öeren, Mario, Robertson, Murray N. ORCID logoORCID: https://orcid.org/0000-0001-9543-7667, Spadavecchio, Vito, Tatsis, Vasileios A., van Hoorn, Willem P., Wade, Alexander D., Whitehead, Thomas M., Willis, Paul and Todd, Matthew H.;
CORE (COnnecting REpositories)