Imperial College London
Alternate

ProfessorRobertGlen

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Chair in Computational Medicine
 
 
 
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Contact

 

+44 (0)20 7594 7912r.glen Website

 
 
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Location

 

362Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Kalash:2018:10.1016/j.ejmech.2018.08.049,
author = {Kalash, L and Cresser-Brown, J and Habchi, J and Morgan, C and Miller, DJ and Glen, RC and Allemann, RK and Bender, A},
doi = {10.1016/j.ejmech.2018.08.049},
journal = {European Journal of Medicinal Chemistry},
pages = {1264--1275},
title = {Structure-based design of allosteric calpain-1 inhibitors populating a novel bioactivity space},
url = {http://dx.doi.org/10.1016/j.ejmech.2018.08.049},
volume = {157},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Dimeric calpains constitute a promising therapeutic target for many diseases such as cardiovascular, neurodegenerative and ischaemic disease. The discovery of selective calpain inhibitors, however, has been extremely challenging. Previously, allosteric inhibitors of calpains, such as PD150606, which included a specific α-mercaptoacrylic acid sub-structure, were reported to bind to the penta-EF hand calcium binding domain, PEF(S) of calpain. Although these are selective to calpains over other cysteine proteases, their mode of action has remained elusive due to their ability to inhibit the active site domain with and without the presence of PEF(S), with similar potency. These findings have led to the question of whether the inhibitory response can be attributed to an allosteric mode of action or alternatively to inhibition at the active site. In order to address this problem, we report a structure-based virtual screening protocol as a novel approach for the discovery of PEF(S) binders that populate a novel chemical space. We have identified compound 1, Vidupiprant, which is shown to bind to the PEF(S) domain by the TNS displacement method, and it exhibited specificity in its allosteric mode of inhibition. Compound 1 inhibited the full-length calpain-1 complex with a higher potency (IC50=7.5μM) than the selective, cell-permeable non-peptide calpain inhibitor, PD150606 (IC50=19.3μM), where the latter also inhibited the active site domain in the absence of PEF(S) (IC50=17.8μM). Hence the method presented here has identified known compounds with a novel allosteric mechanism for the inhibition of calpain-1. We show for the first time that the inhibition of enzyme activity can be attributed to an allosteric mode of action, which may offer improved selectivity and a reduced side-effects profile.
AU  - Kalash,L
AU  - Cresser-Brown,J
AU  - Habchi,J
AU  - Morgan,C
AU  - Miller,DJ
AU  - Glen,RC
AU  - Allemann,RK
AU  - Bender,A
DO  - 10.1016/j.ejmech.2018.08.049
EP  - 1275
PY  - 2018///
SN  - 0223-5234
SP  - 1264
TI  - Structure-based design of allosteric calpain-1 inhibitors populating a novel bioactivity space
T2  - European Journal of Medicinal Chemistry
UR  - http://dx.doi.org/10.1016/j.ejmech.2018.08.049
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000447480000091&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/65181
VL  - 157
ER  -
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