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

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

  • J Med Chem. 2021 Nov 25;64(22):16450-16463. doi: 10.1021/acs.jmedchem.1c00313.
Edwin G Tse 1,  Laksh Aithani 2,  Mark Anderson 3,  Jonathan Cardoso-Silva 4,  Giovanni Cincilla 5,  Gareth J Conduit 6 7,  Mykola Galushka 8,  Davy Guan 9,  Irene Hallyburton 3,  Benedict W J Irwin 7 10,  Kiaran Kirk 11,  Adele M Lehane 11,  Julia C R Lindblom 11,  Raymond Lui 9,  Slade Matthews 9,  James McCulloch 12,  Alice Motion 13,  Ho Leung Ng 14,  Mario Öeren 10,  Murray N Robertson 15,  Vito Spadavecchio 16,  Vasileios A Tatsis 2,  Willem P van Hoorn 2,  Alexander D Wade 7,  Thomas M Whitehead 6,  Paul Willis 17,  Matthew H Todd 1
Affiliations

Affiliations

  • 1 School of Pharmacy, University College London, London WC1N 1AX, U.K.
  • 2 Exscientia Ltd., The Schrödinger Building, Oxford Science Park, Oxford OX4 4GE, U.K.
  • 3 Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
  • 4 Department of Informatics, Faculty of Natural and Mathematical Sciences, King's College London, London WC2B 4BG, U.K.
  • 5 Molomics, Barcelona Science Park, Barcelona 08028, Spain.
  • 6 Intellegens Ltd., Eagle Labs, Chesterton Road, Cambridge CB4 3AZ, U.K.
  • 7 Theory of Condensed Matter Group, Cavendish Laboratories, University of Cambridge, Cambridge CB3 0HE, U.K.
  • 8 Auromind Ltd, 126 Eglantine Avenue, Belfast BT9 6EU, U.K.
  • 9 School of Medical Sciences, The University of Sydney, Sydney, NSW 2006, Australia.
  • 10 Optibrium Ltd. Blenheim House, Denny End Road, Cambridge CB25 9QE, U.K.
  • 11 Research School of Biology, Australian National University, Canberra, ACT 2601, Australia.
  • 12 Kellerberrin, 6 Wharf Rd, Balmain, Sydney, NSW 2041, Australia.
  • 13 School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
  • 14 Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan Kansas 66506, United States.
  • 15 Strathclyde Institute Of Pharmacy And Biomedical Sciences, University of Strathclyde, Glasgow G4 ORE, U.K.
  • 16 Interlinked Therapeutics LLC, Portland, Oregon 97214, United States.
  • 17 Medicines for Malaria Venture, PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15, Switzerland.
PMID: 34748707 DOI: 10.1021/acs.jmedchem.1c00313
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.

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