Structure-based design of allosteric calpain-1 inhibitors populating a novel bioactivity space.
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Authors
Kalash, Leen
Cresser-Brown, Joel
Habchi, Johnny
Morgan, Connor
Miller, David J
Glen, Robert C
Allemann, Rudolf K
Publication Date
2018-09-05Journal Title
Eur J Med Chem
ISSN
0223-5234
Publisher
Elsevier BV
Volume
157
Pages
1264-1275
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Kalash, L., Cresser-Brown, J., Habchi, J., Morgan, C., Miller, D. J., Glen, R. C., Allemann, R. K., & et al. (2018). Structure-based design of allosteric calpain-1 inhibitors populating a novel bioactivity space.. Eur J Med Chem, 157 1264-1275. https://doi.org/10.1016/j.ejmech.2018.08.049
Abstract
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 = 7.5 μM) than the selective, cell-permeable non-peptide calpain inhibitor, PD150606 (IC50 = 19.3 μM), where the latter also inhibited the active site domain in the absence of PEF(S) (IC50 = 17.8 μM). 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.
Keywords
Allosteric inhibition, Calpain-1 inhibitors, Docking, PEF(S), Structure-based design, Allosteric Regulation, Calpain, Dose-Response Relationship, Drug, Drug Design, Glycoproteins, Humans, Molecular Structure, Structure-Activity Relationship
Sponsorship
European Research Council (336159)
Identifiers
External DOI: https://doi.org/10.1016/j.ejmech.2018.08.049
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285030
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