Screening of a Novel Fragment Library with Functional Complexity against Mycobacterium tuberculosis InhA

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....

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Bibliographic Details
Published in:ChemMedChem 2018-04, Vol.13 (7), p.672-677
Main Authors: Prati, Federica, Zuccotto, Fabio, Fletcher, Daniel, Convery, Maire A., Fernandez‐Menendez, Raquel, Bates, Robert, Encinas, Lourdes, Zeng, Jingkun, Chung, Chun‐wa, De Dios Anton, Paco, Mendoza‐Losana, Alfonso, Mackenzie, Claire, Green, Simon R., Huggett, Margaret, Barros, David, Wyatt, Paul G., Ray, Peter C.
Format: Article
Language:English
Subjects:
Antitubercular Agents - chemical synthesis
Antitubercular Agents - chemistry
Bacterial Proteins - antagonists & inhibitors
Bacterial Proteins - chemistry
Communication
Communications
Complexity
Crystallography, X-Ray
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
fragment based drug discovery
Fragmentation
functional group complexity
Functional groups
InhA
Ligands
Models, Molecular
Molecular Structure
Mycobacterium tuberculosis
Mycobacterium tuberculosis - enzymology
Optimization
Oxidoreductases - antagonists & inhibitors
Oxidoreductases - chemistry
Screening
Small Molecule Libraries - chemical synthesis
Small Molecule Libraries - chemistry
Surface Plasmon Resonance
Tuberculosis
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Summary: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. Functional group complexity fragment hits facilitated rapid fragment‐based lead generation against Mycobacterium tuberculosis InhA, to afford novel and potent InhA inhibitors with good ligand efficiency metrics for optimization.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201700774