'Polymorphism-aided' Selective Targeting and Inhibition of Caspase-6 by a Novel Allosteric Inhibitor Towards Efficient Alzheimer's Disease Treatment.
Alzheimer’s disease
C13
Caspase-6
Putative allosteric site
Selective targeting
Single-nucleotide polymorphism
Journal
Cell biochemistry and biophysics
ISSN: 1559-0283
Titre abrégé: Cell Biochem Biophys
Pays: United States
ID NLM: 9701934
Informations de publication
Date de publication:
Sep 2020
Sep 2020
Historique:
received:
31
12
2019
accepted:
17
06
2020
pubmed:
28
6
2020
medline:
18
2
2021
entrez:
28
6
2020
Statut:
ppublish
Résumé
The predominance of Alzheimer's disease (AD) among the aged remains a global challenge. As such, the search for alternative and effective therapeutic options continuous unabated. Among the therapeutic targets explored over the years toward impeding the progression of AD is caspase-6 (Casp6), although selectively targeting Casp6 remains a challenge due to high homology with other members of the caspase family. Methyl 3-[(2,3-dihydro-1-benzofuran-2-yl formamido) methyl]-5-(furan-2-amido) benzoate (C13), a novel allosteric inhibitor, is reportedly shown to exhibit selective inhibition against mutant human Casp6 variants (E35K). However, structural and atomistic insights accounting for the reported inhibitory prowess of C13 remains unresolved. In this study, we seek to unravel the mechanistic selectivity of C13 coupled with the complementary effects of E35K single-nucleotide polymorphism (SNP) relative to Casp6 inhibition. Analyses of binding dynamics revealed that the variant Lysine-35 mediated consistent high-affinity interactions with C13 at the allosteric site, possibly forming the molecular basis of the selectivity of C13 as well as its high binding free energy as estimated. Analysis of residue interaction network around Glu35 and Lys35 revealed prominent residue network distortions in the mutant Casp6 conformation evidenced by a decrease in node degree, reduced number of edges and an increase short in path length relative to a more compact conformation in the wild system. The relatively higher binding free energy of C13 coupled with the stronger intermolecular interactions elicited in the mutant conformation further suggests that the mutation E35K probably favours the inhibitory activity of C13. Further analysis of atomistic changes showed increased C-α atom deviations consistent with structural disorientations in the mutant Casp6. Structural Insights provided could open up a novel paradigm of structure-based design of selective allosteric inhibition of Casp6 towards the treatment of neurodegenerative diseases.
Identifiants
pubmed: 32592127
doi: 10.1007/s12013-020-00927-0
pii: 10.1007/s12013-020-00927-0
doi:
Substances chimiques
Caspase Inhibitors
0
Caspase 6
EC 3.4.22.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
291-299Références
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