Screening of a novel fragment library with functional complexity against Mycobacterium tuberculosis InhA

Federica Prati; Fabio Zuccotto; Daniel Fletcher; Maire A. Convery; Raquel Fernandez-Menendez; Robert Bates; Lourdes Encinas; Jingkun Zeng; Chun-Wa Chung; Paco De Dios Anton; Alfonso Mendoza-Losana; Claire Mackenzie; Simon R. Green; Margaret Huggett; David Barros; Paul G. Wyatt; Peter C. Ray

doi:10.1002/cmdc.201700774

Screening of a novel fragment library with functional complexity against Mycobacterium tuberculosis InhA

Federica Prati, Fabio Zuccotto, Daniel Fletcher, Maire A. Convery, Raquel Fernandez-Menendez, Robert Bates, Lourdes Encinas, Jingkun Zeng, Chun-Wa Chung, Paco De Dios Anton, Alfonso Mendoza-Losana, Claire Mackenzie, Simon R. Green, Margaret Huggett, David Barros, Paul G. Wyatt (Lead / Corresponding author), Peter C. Ray (Lead / Corresponding author)

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

13 Citations (Scopus)

248 Downloads (Pure)

Abstract

Our findings reported herein, provide support for the benefits of including functional group complexity (FGC) within fragments when screening against protein targets such as Mycobacterium tuberculosis InhA. We show that InhA fragment actives with FGC maintained their binding pose during elaboration. Furthermore, weak fragment hits with functional group handles also allowed for facile fragment elaboration to afford novel and potent InhA inhibitors with good ligand efficiency metrics for optimization.

Original language	English
Pages (from-to)	672-677
Number of pages	6
Journal	ChemMedChem
Volume	13
Issue number	7
Early online date	19 Feb 2018
DOIs	https://doi.org/10.1002/cmdc.201700774
Publication status	Published - 6 Apr 2018

Keywords

Journal article
Fragment based drug discovery
Functional group complexity
InhA
Tuberculosis
tuberculosis
fragment based drug discovery
functional group complexity

ASJC Scopus subject areas

Molecular Medicine
Pharmacology, Toxicology and Pharmaceutics(all)
Organic Chemistry

UN SDGs

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

Access to Document

10.1002/cmdc.201700774

Final Published VersionFinal published version, 1.29 MBLicence: CC BY

De-risking Innovative Drug Discovery Projects through Portfolio Management (Confidence in Concept)
Ferguson, M. (Investigator), Woodland, A. (Investigator) & Wyatt, P. (Investigator)
Medical Research Council
1/03/14 → 31/08/15
Project: Research
De-Risking Innovative Drug Discovery Projects Through Portfolio Management
Ferguson, M. (Investigator) & Wyatt, P. (Investigator)
Medical Research Council
1/01/13 → 30/06/14
Project: Research

Cite this

Prati, F., Zuccotto, F., Fletcher, D., Convery, M. A., Fernandez-Menendez, R., Bates, R., Encinas, L., Zeng, J., Chung, C.-W., De Dios Anton, P., Mendoza-Losana, A., Mackenzie, C., Green, S. R., Huggett, M., Barros, D., Wyatt, P. G., & Ray, P. C. (2018). Screening of a novel fragment library with functional complexity against Mycobacterium tuberculosis InhA. ChemMedChem, 13(7), 672-677. https://doi.org/10.1002/cmdc.201700774

@article{e99e98ae43544b16a0306a9ca399acdb,

title = "Screening of a novel fragment library with functional complexity against Mycobacterium tuberculosis InhA",

abstract = "Our findings reported herein, provide support for the benefits of including functional group complexity (FGC) within fragments when screening against protein targets such as Mycobacterium tuberculosis InhA. We show that InhA fragment actives with FGC maintained their binding pose during elaboration. Furthermore, weak fragment hits with functional group handles also allowed for facile fragment elaboration to afford novel and potent InhA inhibitors with good ligand efficiency metrics for optimization.",

keywords = "Journal article, Fragment based drug discovery , Functional group complexity , InhA, Tuberculosis, tuberculosis, fragment based drug discovery, functional group complexity",

author = "Federica Prati and Fabio Zuccotto and Daniel Fletcher and Convery, {Maire A.} and Raquel Fernandez-Menendez and Robert Bates and Lourdes Encinas and Jingkun Zeng and Chun-Wa Chung and {De Dios Anton}, Paco and Alfonso Mendoza-Losana and Claire Mackenzie and Green, {Simon R.} and Margaret Huggett and David Barros and Wyatt, {Paul G.} and Ray, {Peter C.}",

note = "The research leading to these results was co-funded by the Tres Cantos Open Lab Foundation (project code TC162) and the European Union{\textquoteright}s Seventh Frame-work Programme (grant agreement no. 291799). Fragment screening was funded by a MRC-CinC grant (no. MC_PC_13061) to the University of Dundee.",

year = "2018",

month = apr,

day = "6",

doi = "10.1002/cmdc.201700774",

language = "English",

volume = "13",

pages = "672--677",

journal = "ChemMedChem",

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Prati, F, Zuccotto, F, Fletcher, D, Convery, MA, Fernandez-Menendez, R, Bates, R, Encinas, L, Zeng, J, Chung, C-W, De Dios Anton, P, Mendoza-Losana, A, Mackenzie, C , Green, SR, Huggett, M, Barros, D, Wyatt, PG & Ray, PC 2018, 'Screening of a novel fragment library with functional complexity against Mycobacterium tuberculosis InhA', ChemMedChem, vol. 13, no. 7, pp. 672-677. https://doi.org/10.1002/cmdc.201700774

TY - JOUR

T1 - Screening of a novel fragment library with functional complexity against Mycobacterium tuberculosis InhA

AU - Prati, Federica

AU - Zuccotto, Fabio

AU - Fletcher, Daniel

AU - Convery, Maire A.

AU - Fernandez-Menendez, Raquel

AU - Bates, Robert

AU - Encinas, Lourdes

AU - Zeng, Jingkun

AU - Chung, Chun-Wa

AU - De Dios Anton, Paco

AU - Mendoza-Losana, Alfonso

AU - Mackenzie, Claire

AU - Green, Simon R.

AU - Huggett, Margaret

AU - Barros, David

AU - Wyatt, Paul G.

AU - Ray, Peter C.

N1 - The research leading to these results was co-funded by the Tres Cantos Open Lab Foundation (project code TC162) and the European Union’s Seventh Frame-work Programme (grant agreement no. 291799). Fragment screening was funded by a MRC-CinC grant (no. MC_PC_13061) to the University of Dundee.

PY - 2018/4/6

Y1 - 2018/4/6

N2 - Our findings reported herein, provide support for the benefits of including functional group complexity (FGC) within fragments when screening against protein targets such as Mycobacterium tuberculosis InhA. We show that InhA fragment actives with FGC maintained their binding pose during elaboration. Furthermore, weak fragment hits with functional group handles also allowed for facile fragment elaboration to afford novel and potent InhA inhibitors with good ligand efficiency metrics for optimization.

AB - Our findings reported herein, provide support for the benefits of including functional group complexity (FGC) within fragments when screening against protein targets such as Mycobacterium tuberculosis InhA. We show that InhA fragment actives with FGC maintained their binding pose during elaboration. Furthermore, weak fragment hits with functional group handles also allowed for facile fragment elaboration to afford novel and potent InhA inhibitors with good ligand efficiency metrics for optimization.

KW - Journal article

KW - Fragment based drug discovery

KW - Functional group complexity

KW - InhA

KW - Tuberculosis

KW - tuberculosis

KW - fragment based drug discovery

KW - functional group complexity

U2 - 10.1002/cmdc.201700774

DO - 10.1002/cmdc.201700774

M3 - Article

C2 - 29399991

SN - 1860-7179

VL - 13

SP - 672

EP - 677

JO - ChemMedChem

JF - ChemMedChem

IS - 7

ER -

Screening of a novel fragment library with functional complexity against Mycobacterium tuberculosis InhA

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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De-risking Innovative Drug Discovery Projects through Portfolio Management (Confidence in Concept)

De-Risking Innovative Drug Discovery Projects Through Portfolio Management

Cite this