Affiliation:
1. Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa
Abstract
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:
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:
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.
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.
Publisher
Bentham Science Publishers Ltd.
Subject
Pharmaceutical Science,Biotechnology
Cited by
3 articles.
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