An Open Drug Discovery Competition: Experimental Validation of Predictive Models in a Series of Novel Antimalarials

Edwin G. Tse; Laksh Aithani; Mark Anderson; Jonathan Cardoso-Silva; Giovanni Cincilla; Gareth J. Conduit; Mykola Galushka; Davy Guan; Irene Hallyburton; Benedict W.J. Irwin; Kiaran Kirk; Adele M. Lehane; Julia C.R. Lindblom; Raymond Lui; Slade Matthews; James McCulloch; Alice Motion; Ho Leung Ng; Mario Öeren; Murray N. Robertson; Vito Spadavecchio; Vasileios A. Tatsis; Willem P. Van Hoorn; Alexander D. Wade; Thomas M. Whitehead; Paul Willis; Matthew H. Todd

doi:10.1021/acs.jmedchem.1c00313

An Open Drug Discovery Competition: Experimental Validation of Predictive Models in a Series of Novel Antimalarials

Edwin G. Tse, Laksh Aithani, Mark Anderson, Jonathan Cardoso-Silva, Giovanni Cincilla, Gareth J. Conduit, Mykola Galushka, Davy Guan, Irene Hallyburton, Benedict W.J. Irwin, Kiaran Kirk, Adele M. Lehane, Julia C.R. Lindblom, Raymond Lui, Slade Matthews, James McCulloch, Alice Motion, Ho Leung Ng, Mario Öeren, Murray N. RobertsonVito Spadavecchio, Vasileios A. Tatsis, Willem P. Van Hoorn, Alexander D. Wade, Thomas M. Whitehead, Paul Willis, Matthew H. Todd^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	16450-16463
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	22
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00313
Publication status	Published - 25 Nov 2021

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Tse, E. G., Aithani, L., Anderson, M., Cardoso-Silva, J., Cincilla, G., Conduit, G. J., Galushka, M., Guan, D., Hallyburton, I., Irwin, B. W. J., Kirk, K., Lehane, A. M., Lindblom, J. C. R., Lui, R., Matthews, S., McCulloch, J., Motion, A., Ng, H. L., Öeren, M., ... Todd, M. H. (2021). An Open Drug Discovery Competition: Experimental Validation of Predictive Models in a Series of Novel Antimalarials. Journal of Medicinal Chemistry, 64(22), 16450-16463. https://doi.org/10.1021/acs.jmedchem.1c00313

@article{68bd6fea95664a7e94065a7d7abb623c,

title = "An Open Drug Discovery Competition: Experimental Validation of Predictive Models in a Series of Novel Antimalarials",

abstract = "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.",

author = "Tse, {Edwin G.} and Laksh Aithani and Mark Anderson and Jonathan Cardoso-Silva and Giovanni Cincilla and Conduit, {Gareth J.} and Mykola Galushka and Davy Guan and Irene Hallyburton and Irwin, {Benedict W.J.} and Kiaran Kirk and Lehane, {Adele M.} and Lindblom, {Julia C.R.} and Raymond Lui and Slade Matthews and James McCulloch and Alice Motion and Ng, {Ho Leung} and Mario {\"O}eren and Robertson, {Murray N.} and Vito Spadavecchio and Tatsis, {Vasileios A.} and {Van Hoorn}, {Willem P.} and Wade, {Alexander D.} and Whitehead, {Thomas M.} and Paul Willis and Todd, {Matthew H.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Published by American Chemical Society.",

year = "2021",

month = nov,

day = "25",

doi = "10.1021/acs.jmedchem.1c00313",

language = "English",

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Tse, EG, Aithani, L, Anderson, M, Cardoso-Silva, J, Cincilla, G, Conduit, GJ, Galushka, M, Guan, D, Hallyburton, I, Irwin, BWJ, Kirk, K , Lehane, AM, Lindblom, JCR, Lui, R, Matthews, S, McCulloch, J, Motion, A, Ng, HL, Öeren, M, Robertson, MN, Spadavecchio, V, Tatsis, VA, Van Hoorn, WP, Wade, AD, Whitehead, TM, Willis, P & Todd, MH 2021, 'An Open Drug Discovery Competition: Experimental Validation of Predictive Models in a Series of Novel Antimalarials', Journal of Medicinal Chemistry, vol. 64, no. 22, pp. 16450-16463. https://doi.org/10.1021/acs.jmedchem.1c00313

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.

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.

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U2 - 10.1021/acs.jmedchem.1c00313

DO - 10.1021/acs.jmedchem.1c00313

M3 - Article

SN - 0022-2623

VL - 64

SP - 16450

EP - 16463

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 22

ER -

An Open Drug Discovery Competition: Experimental Validation of Predictive Models in a Series of Novel Antimalarials

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