Revisiting the Plasmodium falciparum druggable genome using predicted structures and data mining

Identification of novel drug targets is a key component of modern drug discovery. While antimalarial targets are often identified through the mechanism of action studies on phenotypically derived inhibitors, this method tends to be time- and resource-consuming. The discoverable target space is also constrained by existing compound libraries and phenotypic assay conditions. Leveraging recent advances in protein structure prediction, we systematically assessed the <i>Plasmodium falciparum</i> genome and identified 867 candidate protein targets with evidence of small-molecule binding and blood-stage essentiality. Of these, 540 proteins showed strong essentiality evidence and lack inhibitors that have progressed to clinical trials. Expert review and rubric-based scoring of this subset based on additional criteria such as selectivity, structural information, and assay developability yielded 27 high-priority antimalarial target candidates. This study also provides a genome-wide data resource for <i>P. falciparum</i> and implements a generalizable framework for systematically evaluating and prioritizing novel pathogenic disease targets.

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Publication Details

Journal
npj Drug Discovery.
Published
2025-03-04
DOI
https://doi.org/10.1038/s44386-025-00006-5
Citations
8
Primary Topic
vaccines and immunoinformatics approaches
Type
article
Field-Weighted Citation Impact
6.45

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article

Revisiting the Plasmodium falciparum druggable genome using predicted structures and data mining

Igor M. R. Moura, Koen J. Dechering, Francisco‐Javier Gamo, John Okombo et al.
8 citations
npj Drug Discovery.
vaccines and immunoinformatics approaches
6.45
article

Revisiting the Plasmodium falciparum druggable genome using predicted structures and data mining

Igor M. R. Moura, Koen J. Dechering, Francisco‐Javier Gamo, John Okombo, Erika L. Flannery, Krittikorn Kümpornsin, Dyann F. Wirth, Barbara Forte, Brice Campo, Karen L. Lobb, Luma G. Magalhães, B. Somsen, Daniel E. Goldberg, Jair L. Siqueira-Neto, Ian H. Gilbert, Lauren B. Coulson, N. Connor Payne, Case W. McNamara, Greg Durst, Vandana Thathy, Lisl Y. Esherick, Jacquin C. Niles, Rumin Zhang, Michael K. Gilson, Krypton Carolino, Srinivasa P. S. Rao, Tiqing Liu, Madeline A. Farringer, Kyle J McLean, Karla P. Godinez‐Macias, David A. Fidock, Eva S. Istvan, James Duffy, Beatriz Baragaña, Elizabeth A. Winzeler, Amanda K. Lukens, Robert L. Summers, Lyn‐Marié Birkholtz, Daisy Chen, Alfred W. Bronkhorst, Andrew Plater, Selina Bopp, Xiu Cheng, Anil Kumar Gupta, Lee M, Tiantian Jiang, Anna Adam, John Wallis, Miles G. Siegel
article en
8 citations

Abstract

Identification of novel drug targets is a key component of modern drug discovery. While antimalarial targets are often identified through the mechanism of action studies on phenotypically derived inhibitors, this method tends to be time- and resource-consuming. The discoverable target space is also constrained by existing compound libraries and phenotypic assay conditions. Leveraging recent advances in protein structure prediction, we systematically assessed the <i>Plasmodium falciparum</i> genome and identified 867 candidate protein targets with evidence of small-molecule binding and blood-stage essentiality. Of these, 540 proteins showed strong essentiality evidence and lack inhibitors that have progressed to clinical trials. Expert review and rubric-based scoring of this subset based on additional criteria such as selectivity, structural information, and assay developability yielded 27 high-priority antimalarial target candidates. This study also provides a genome-wide data resource for <i>P. falciparum</i> and implements a generalizable framework for systematically evaluating and prioritizing novel pathogenic disease targets.

npj Drug Discovery.Vol. 2(1)
Broad Institute (US), Scripps Research Institute (US), Boston Children's Hospital (US), Harvard University (US), University of Cape Town (ZA), University of Dundee (GB), Universidade de São Paulo (BR), Washington University in St. Louis (US), Columbia University Irving Medical Center (US), University of California San Diego (US), Novartis (United States) (US), Wellcome Centre for Anti-Infectives Research (GB), California Institute for Biomedical Research (US), Panorama Research (United States) (US), GlaxoSmithKline (Spain) (ES), Center for Systems Biology (US), TropIQ Health Sciences (NL), Medicines for Malaria Venture (CH), Massachusetts Institute of Technology (US), University of Montana (US), University of Pretoria (ZA)
Bill and Melinda Gates Foundation, Fundação de Amparo à Pesquisa do Estado de São Paulo, National Institutes of Health
Openalex Percentile: Top 3%
vaccines and immunoinformatics approaches
6.45
DOIOpen Access PDFOpenAlex
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