TY - JOUR
T1 - An Open Drug Discovery Competition
T2 - Experimental Validation of Predictive Models in a Series of Novel Antimalarials
AU - Tse, Edwin G.
AU - Aithani, Laksh
AU - Anderson, Mark
AU - Cardoso-Silva, Jonathan
AU - Cincilla, Giovanni
AU - Conduit, Gareth J.
AU - Galushka, Mykola
AU - Guan, Davy
AU - Hallyburton, Irene
AU - Irwin, Benedict W. J.
AU - Kirk, Kiaran
AU - Lehane, Adele M.
AU - Lindblom, Julia C. R.
AU - Lui, Raymond
AU - Matthews, Slade
AU - McCulloch, James
AU - Motion, Alice
AU - Ng, Ho Leung
AU - Öeren, Mario
AU - Robertson, Murray N.
AU - Spadavecchio, Vito
AU - Tatsis, Vasileios A.
AU - van Hoorn, Willem P.
AU - Wade, Alexander D.
AU - Whitehead, Thomas M.
AU - Willis, Paul
AU - Todd, Matthew H.
N1 - Funding Information:
This work has been supported by the Artificial Intelligence and Augmented Intelligence for Automated Investigations for Scientific Discovery Network+, which has been funded by EPSRC (EP/S000356/1), the Australian Research Council (LP150101226), the Medicines for Malaria Venture (RD/11/0040) and University College London for funding (to M.H.T.), the US National Science Foundation (1833181) (to H.L.N.), the EPSRC Centre for Doctoral Training in Computational Methods for Materials Science /(EPL015552/2) (to A.D.W.), the EPSRC Future Continuous Manufacturing and Advanced Crystallization (CMAC) Research Hub (EP/L015552/1) (to M.N.R.), and the Royal Society (to G.J.C.).
PY - 2021/11/25
Y1 - 2021/11/25
N2 - The Open Source Malaria (OSM) consortium is developing compounds that kill the human malaria parasite, Plasmodium falciparum, by targeting PfATP4, an essential ion pump on the parasite surface. The structure of PfATP4 has not been determined. Here, we describe a public competition created to develop a predictive model for the identification of PfATP4 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.
AB - The Open Source Malaria (OSM) consortium is developing compounds that kill the human malaria parasite, Plasmodium falciparum, by targeting PfATP4, an essential ion pump on the parasite surface. The structure of PfATP4 has not been determined. Here, we describe a public competition created to develop a predictive model for the identification of PfATP4 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.
KW - Molecular modeling
KW - Layers
KW - Parasites
KW - Chromatography
UR - http://www.scopus.com/inward/record.url?scp=85119424783&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c00313
DO - 10.1021/acs.jmedchem.1c00313
M3 - Article
C2 - 34748707
SN - 0022-2623
VL - 64
SP - 16450
EP - 16463
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 22
ER -