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Issue 44, 2014
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Approaches to design non-covalent inhibitors for human granzyme B (hGrB)

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Abstract

A structure-based design campaign for non-covalent small molecule inhibitors of human granzyme B was carried out by means of a virtual screening strategy employing three constraints and probe site-mapping with FTMAP to identify ligand “hot spots”. In addition, new scaffolds of diverse structures were subsequently explored with ROCS shape-based superposition methods, following by Glide SP docking, induced fit docking and analysis of QikProp molecular properties. Novel classes of moderately active small molecule blockers (≥25 μM IC50 values) from commercially available libraries were identified, and three novel scaffolds have been synthesized by multi-step procedures. Furthermore, we provide an example of a comprehensive structure-based drug discovery approach to non-covalent inhibitors that relies on the X-ray structure of a covalently bound ligand and suggest that the design path may be compromised by alternative and unknown binding poses.

Graphical abstract: Approaches to design non-covalent inhibitors for human granzyme B (hGrB)

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Supplementary files

Article information


Submitted
03 Sep 2014
Accepted
22 Sep 2014
First published
23 Sep 2014

Org. Biomol. Chem., 2014,12, 8952-8965
Article type
Paper

Approaches to design non-covalent inhibitors for human granzyme B (hGrB)

M. Kim, L. A. Buisson, D. A. Heathcote, H. Hu, D. C. Braddock, A. G. M. Barrett, P. G. Ashton-Rickardt and J. P. Snyder, Org. Biomol. Chem., 2014, 12, 8952
DOI: 10.1039/C4OB01874E

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