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

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

doi:10.21203/rs.3.rs-5412515/v1

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

Karla P. Godinez-Macias
, Daisy Chen
, J. Lincoln Wallis
, Miles G. Siegel
, Anna Adam
, Selina Bopp
, Krypton Carolino
, Lauren B. Coulson
, Greg Durst
, Vandana Thathy
, Lisl Esherick
, Madeline A. Farringer
, Erika L. Flannery
, Barbara Forte
, Tiqing Liu
, Luma Godoy Magalhaes
, Anil K. Gupta
, Eva S. Istvan
, Tiantian Jiang
, Krittikorn Kumpornsin

Karen Lobb, Kyle McLean, Igor M. R. Moura, John Okombo, N. Connor Payne, Andrew Plater, Srinivasa P S Rao, Jair L. Siqueira-Neto, Bente A. Somsen, Robert L. Summers, Rumin Zhang, Michael K. Gilson, Francisco-Javier Gamo, Brice Campo, Beatriz Baragaña, James Duffy, Ian H. Gilbert, Amanda K. Lukens, Koen J. Dechering, Jacquin C. Niles, Case W. McNamara, Xiu Cheng, Lyn-Marie Birkholtz, Alfred W. Bronkhorst, David A. Fidock, Dyann F. Wirth, Daniel E. Goldberg, Marcus C.S. Lee, Elizabeth A. Winzeler (Lead / Corresponding author)

Research output: Working paper/Preprint › Preprint

Abstract

The identification of novel drug targets for the purpose of designing small molecule inhibitors is key component to modern drug discovery. In malaria parasites, discoveries of antimalarial targets have primarily occurred retroactively by investigating the mode of action of compounds found through phenotypic screens. Although this method has yielded many promising candidates, it is time- and resource-consuming and misses targets not captured by existing antimalarial compound libraries and phenotypic assay conditions. Leveraging recent advances in protein structure prediction and data mining, we systematically assessed the Plasmodium falciparum genome for proteins amenable to target-based drug discovery, identifying 867 candidate 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 67 high priority candidates. This study also provides a genome-wide data resource and implements a generalizable framework for systematically evaluating and prioritizing novel pathogenic disease targets.

Original language	English
Publisher	Research Square
Number of pages	32
DOIs	https://doi.org/10.21203/rs.3.rs-5412515/v1
Publication status	Published - 26 Nov 2024

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.21203/rs.3.rs-5412515/v1Licence: CC BY

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Godinez-Macias, K. P., Chen, D., Wallis, J. L., Siegel, M. G., Adam, A., Bopp, S., Carolino, K., Coulson, L. B., Durst, G., Thathy, V., Esherick, L., Farringer, M. A., Flannery, E. L., Forte, B., Liu, T., Magalhaes, L. G., Gupta, A. K., Istvan, E. S., Jiang, T., ... Winzeler, E. A. (2024). Revisiting the Plasmodium falciparum druggable genome using predicted structures and data mining. Research Square. https://doi.org/10.21203/rs.3.rs-5412515/v1

@techreport{844524aa902b4908a72f9270a6ca0926,

title = "Revisiting the Plasmodium falciparum druggable genome using predicted structures and data mining",

abstract = "The identification of novel drug targets for the purpose of designing small molecule inhibitors is key component to modern drug discovery. In malaria parasites, discoveries of antimalarial targets have primarily occurred retroactively by investigating the mode of action of compounds found through phenotypic screens. Although this method has yielded many promising candidates, it is time- and resource-consuming and misses targets not captured by existing antimalarial compound libraries and phenotypic assay conditions. Leveraging recent advances in protein structure prediction and data mining, we systematically assessed the Plasmodium falciparum genome for proteins amenable to target-based drug discovery, identifying 867 candidate 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 67 high priority candidates. This study also provides a genome-wide data resource and implements a generalizable framework for systematically evaluating and prioritizing novel pathogenic disease targets. ",

author = "Godinez-Macias, \{Karla P.\} and Daisy Chen and Wallis, \{J. Lincoln\} and Siegel, \{Miles G.\} and Anna Adam and Selina Bopp and Krypton Carolino and Coulson, \{Lauren B.\} and Greg Durst and Vandana Thathy and Lisl Esherick and Farringer, \{Madeline A.\} and Flannery, \{Erika L.\} and Barbara Forte and Tiqing Liu and Magalhaes, \{Luma Godoy\} and Gupta, \{Anil K.\} and Istvan, \{Eva S.\} and Tiantian Jiang and Krittikorn Kumpornsin and Karen Lobb and Kyle McLean and Moura, \{Igor M. R.\} and John Okombo and Payne, \{N. Connor\} and Andrew Plater and Rao, \{Srinivasa P S\} and Siqueira-Neto, \{Jair L.\} and Somsen, \{Bente A.\} and Summers, \{Robert L.\} and Rumin Zhang and Gilson, \{Michael K.\} and Francisco-Javier Gamo and Brice Campo and Beatriz Baraga{\~n}a and James Duffy and Gilbert, \{Ian H.\} and Lukens, \{Amanda K.\} and Dechering, \{Koen J.\} and Niles, \{Jacquin C.\} and McNamara, \{Case W.\} and Xiu Cheng and Lyn-Marie Birkholtz and Bronkhorst, \{Alfred W.\} and Fidock, \{David A.\} and Wirth, \{Dyann F.\} and Goldberg, \{Daniel E.\} and Lee, \{Marcus C.S.\} and Winzeler, \{Elizabeth A.\}",

year = "2024",

month = nov,

day = "26",

doi = "10.21203/rs.3.rs-5412515/v1",

language = "English",

publisher = "Research Square",

address = "United States",

type = "WorkingPaper",

institution = "Research Square",

}

Godinez-Macias, KP, Chen, D, Wallis, JL, Siegel, MG, Adam, A, Bopp, S, Carolino, K, Coulson, LB, Durst, G, Thathy, V, Esherick, L, Farringer, MA, Flannery, EL, Forte, B, Liu, T, Magalhaes, LG, Gupta, AK, Istvan, ES, Jiang, T, Kumpornsin, K, Lobb, K, McLean, K, Moura, IMR, Okombo, J, Payne, NC, Plater, A, Rao, SPS, Siqueira-Neto, JL, Somsen, BA, Summers, RL, Zhang, R, Gilson, MK, Gamo, F-J, Campo, B, Baragaña, B, Duffy, J, Gilbert, IH, Lukens, AK, Dechering, KJ, Niles, JC, McNamara, CW, Cheng, X, Birkholtz, L-M, Bronkhorst, AW, Fidock, DA, Wirth, DF, Goldberg, DE, Lee, MCS & Winzeler, EA 2024 'Revisiting the Plasmodium falciparum druggable genome using predicted structures and data mining' Research Square. https://doi.org/10.21203/rs.3.rs-5412515/v1

TY - UNPB

T1 - Revisiting the Plasmodium falciparum druggable genome using predicted structures and data mining

AU - Godinez-Macias, Karla P.

AU - Chen, Daisy

AU - Wallis, J. Lincoln

AU - Siegel, Miles G.

AU - Adam, Anna

AU - Bopp, Selina

AU - Carolino, Krypton

AU - Coulson, Lauren B.

AU - Durst, Greg

AU - Thathy, Vandana

AU - Esherick, Lisl

AU - Farringer, Madeline A.

AU - Flannery, Erika L.

AU - Forte, Barbara

AU - Liu, Tiqing

AU - Magalhaes, Luma Godoy

AU - Gupta, Anil K.

AU - Istvan, Eva S.

AU - Jiang, Tiantian

AU - Kumpornsin, Krittikorn

AU - Lobb, Karen

AU - McLean, Kyle

AU - Moura, Igor M. R.

AU - Okombo, John

AU - Payne, N. Connor

AU - Plater, Andrew

AU - Rao, Srinivasa P S

AU - Siqueira-Neto, Jair L.

AU - Somsen, Bente A.

AU - Summers, Robert L.

AU - Zhang, Rumin

AU - Gilson, Michael K.

AU - Gamo, Francisco-Javier

AU - Campo, Brice

AU - Baragaña, Beatriz

AU - Duffy, James

AU - Gilbert, Ian H.

AU - Lukens, Amanda K.

AU - Dechering, Koen J.

AU - Niles, Jacquin C.

AU - McNamara, Case W.

AU - Cheng, Xiu

AU - Birkholtz, Lyn-Marie

AU - Bronkhorst, Alfred W.

AU - Fidock, David A.

AU - Wirth, Dyann F.

AU - Goldberg, Daniel E.

AU - Lee, Marcus C.S.

AU - Winzeler, Elizabeth A.

PY - 2024/11/26

Y1 - 2024/11/26

N2 - The identification of novel drug targets for the purpose of designing small molecule inhibitors is key component to modern drug discovery. In malaria parasites, discoveries of antimalarial targets have primarily occurred retroactively by investigating the mode of action of compounds found through phenotypic screens. Although this method has yielded many promising candidates, it is time- and resource-consuming and misses targets not captured by existing antimalarial compound libraries and phenotypic assay conditions. Leveraging recent advances in protein structure prediction and data mining, we systematically assessed the Plasmodium falciparum genome for proteins amenable to target-based drug discovery, identifying 867 candidate 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 67 high priority candidates. This study also provides a genome-wide data resource and implements a generalizable framework for systematically evaluating and prioritizing novel pathogenic disease targets.

AB - The identification of novel drug targets for the purpose of designing small molecule inhibitors is key component to modern drug discovery. In malaria parasites, discoveries of antimalarial targets have primarily occurred retroactively by investigating the mode of action of compounds found through phenotypic screens. Although this method has yielded many promising candidates, it is time- and resource-consuming and misses targets not captured by existing antimalarial compound libraries and phenotypic assay conditions. Leveraging recent advances in protein structure prediction and data mining, we systematically assessed the Plasmodium falciparum genome for proteins amenable to target-based drug discovery, identifying 867 candidate 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 67 high priority candidates. This study also provides a genome-wide data resource and implements a generalizable framework for systematically evaluating and prioritizing novel pathogenic disease targets.

U2 - 10.21203/rs.3.rs-5412515/v1

DO - 10.21203/rs.3.rs-5412515/v1

M3 - Preprint

C2 - 39649165

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

PB - Research Square

ER -

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

Abstract

UN SDGs

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