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. 2018 Apr 6;13(7):672-677.
doi: 10.1002/cmdc.201700774. Epub 2018 Feb 19.

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

Federica Prati  1   2 , Fabio Zuccotto  1 , Daniel Fletcher  1 , Maire A Convery  3 , Raquel Fernandez-Menendez  2 , Robert Bates  2 , Lourdes Encinas  2 , Jingkun Zeng  3 , Chun-Wa Chung  3 , Paco De Dios Anton  2 , Alfonso Mendoza-Losana  2 , Claire Mackenzie  1 , Simon R Green  1 , Margaret Huggett  1 , David Barros  2 , Paul G Wyatt  1 , Peter C Ray  1
Affiliations

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

Federica Prati et al. ChemMedChem. .

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: InhA; fragment based drug discovery; functional group complexity; tuberculosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
INH and selected advanced direct InhA inhibitors 1–3.
Figure 2
Figure 2
A) Fragment screening library composition. B) 149 STD‐NMR hits vs. their source. C) 32 STD‐NMR hits with reduction of NADH peak intensity vs. their source.
Figure 3
Figure 3
32 STD NMR hits 4–35. FGC are in blue; known InhA cores are in red. Crystal structures were obtained for fragments in bold.
Figure 4
Figure 4
Crystal structures showing novel InhA–NADH–ligand complexes: A) overlay for fragments 12 (yellow) and 24 (blue), B) merged urea lead 37, and C) overlay for fragment 40 (blue) and fused lead 41 (yellow).
Figure 5
Figure 5
FBLG strategies: merging and growing.
Figure 6
Figure 6
Crystal structures showing novel InhA–NADH–ligand complexes: A) overlay for fragments 4 (blue) and 9 (yellow), B) overlay of 34 (yellow) with the published advanced lead 45 (blue; PDB ID: http://www.rcsb.org/pdb/explore/explore.do?structureId=5JFO), and C) overlay for fragment 9 (yellow) and lead 46 (blue).
Figure 7
Figure 7
Design strategy for pyrazoles 46 and 47.
See this image and copyright information in PMC

References

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