In Silico Repurposing of J147 for Neonatal Encephalopathy Treatment: Exploring Molecular Mechanisms of Mutant Mitochondrial ATP Synthase.
Allosteric Regulation
Brain Diseases
/ drug therapy
Computational Biology
Computer Simulation
Curcumin
/ analogs & derivatives
Drug Design
Drug Repositioning
Genetic Diseases, Inborn
/ drug therapy
Humans
Mitochondria
/ enzymology
Mitochondrial Proton-Translocating ATPases
/ antagonists & inhibitors
Molecular Dynamics Simulation
Mutation
J147
Mitochondrial ATP synthase
complex V deficiency
mutation
neonatal encephalopathy
wild-type enzyme
Journal
Current pharmaceutical biotechnology
ISSN: 1873-4316
Titre abrégé: Curr Pharm Biotechnol
Pays: Netherlands
ID NLM: 100960530
Informations de publication
Date de publication:
2020
2020
Historique:
received:
21
12
2019
revised:
25
03
2020
accepted:
08
05
2020
pubmed:
1
7
2020
medline:
8
1
2021
entrez:
30
6
2020
Statut:
ppublish
Résumé
Neonatal Encephalopathy (NE) is a mitochondrial ATP synthase (mATPase) disease, which results in the death of infants. The case presented here is reportedly caused by complex V deficiency as a result of mutation of Arginine to Cysteine at residue 329 in the mATPase. A recent breakthrough was the discovery of J147, which targets mATPase in the treatment of Alzheimer's disease. Based on the concepts of computational target-based drug design, this study investigated the possibility of employing J147 as a viable candidate in the treatment of NE. The structural dynamic implications of this drug on the mutated enzyme are yet to be elucidated. Hence, integrative molecular dynamics simulations and thermodynamic calculations were employed to investigate the activity of J147 on the mutated enzyme in comparison to its already established inhibitory activity on the wild-type enzyme. A correlated structural trend occurred between the wild-type and mutant systems whereby all the systems exhibited an overall conformational transition. Equal observations in favorable free binding energies further substantiated uniformity in the mobility, and residual fluctuation of the wild-type and mutant systems. The similarity in the binding landscape suggests that J147 could as well modulate mutant mATPase activity in addition to causing structural modifications in the wild-type enzyme. Findings suggest that J147 can stabilize the mutant protein and restore it to a similar structural state as the wild-type which depicts functionality. These details could be employed in drug design for potential drug resistance cases due to mATPase mutations that may present in the future.
Sections du résumé
BACKGROUND
BACKGROUND
Neonatal Encephalopathy (NE) is a mitochondrial ATP synthase (mATPase) disease, which results in the death of infants. The case presented here is reportedly caused by complex V deficiency as a result of mutation of Arginine to Cysteine at residue 329 in the mATPase. A recent breakthrough was the discovery of J147, which targets mATPase in the treatment of Alzheimer's disease. Based on the concepts of computational target-based drug design, this study investigated the possibility of employing J147 as a viable candidate in the treatment of NE.
OBJECTIVE/METHODS
OBJECTIVE
The structural dynamic implications of this drug on the mutated enzyme are yet to be elucidated. Hence, integrative molecular dynamics simulations and thermodynamic calculations were employed to investigate the activity of J147 on the mutated enzyme in comparison to its already established inhibitory activity on the wild-type enzyme.
RESULTS
RESULTS
A correlated structural trend occurred between the wild-type and mutant systems whereby all the systems exhibited an overall conformational transition. Equal observations in favorable free binding energies further substantiated uniformity in the mobility, and residual fluctuation of the wild-type and mutant systems. The similarity in the binding landscape suggests that J147 could as well modulate mutant mATPase activity in addition to causing structural modifications in the wild-type enzyme.
CONCLUSION
CONCLUSIONS
Findings suggest that J147 can stabilize the mutant protein and restore it to a similar structural state as the wild-type which depicts functionality. These details could be employed in drug design for potential drug resistance cases due to mATPase mutations that may present in the future.
Identifiants
pubmed: 32598251
pii: CPB-EPUB-107759
doi: 10.2174/1389201021666200628152246
doi:
Substances chimiques
J147
0
Mitochondrial Proton-Translocating ATPases
EC 3.6.3.-
Curcumin
IT942ZTH98
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1551-1566Informations de copyright
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