Abstract:
Huntington’s disease (HD) is a neurodegenerative disorder, caused by the expansion of CAG
repeats in the Huntingtin gene. Many recent studies have suggested that calcium dyshomeostasis
is a one of the major causative factors in HD pathogenesis. It have been advocated that Mutant
Huntingtin (mHTT) affects calcium signaling by sensitizing Inositol 1,4,5 triphosphate receptors
(IP3R) to activation by Inositol 1,4,5 triphosphate (IP3). Additionally, Polyglutamine expansion
in HTT leads to neuronal death of Medium Spiny Neurons (MSNs) in the striatum due to
sensitization of IP3R. Although the genetic cause of the disease has been known for a long time,
no effective therapeutic strategy has been developed so far due to complexity of the disease
mechanistic and regulation. In this research, we constructed a Biological Regulatory Network
(BRN) and performed calcium dyshomeostasis target validation of Huntingtin protein.
Subsequently, molecular docking and molecular dynamics simulations were performed to develop
potential therapeutic interventions against the identified drug targets for Huntington’s disease. The
Molecular Docking studies are employed on HTT protein with PDB ID 6X9O with binding site
residues Asp2737, Glu2738, Asp2758, Lys2759, Glu3106, Glu3107, and Leu3108. Four potential
ligands namely, Gabapentin, Mannitol, Paroxetine and an undefined ligand, were selected from
the curated dataset of sixty-nine inhibitors, for further MD Simulations. The average RMSD values
for these complexes are 0.58, 0.28, 0.29 and 0.29 respectively while the average RMSF values are
0.25, 0.43, 0.25 and 0.27 respectively. These findings revealed that these complexes maintained
stable conformations with high flexibility at functional sites that suggests the potential therapeutic
efficacy in modulation of the pathological aspects of HD. Among these four ligand complexes, the
inhibitor Mannitol showed the highest RMSD value indicating the highest stability compared to
the others. Our study was able to validate HTT as potential drug target and comprehend the
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molecular mechanism of the disease which can assist in developing novel therapeutic strategies
for the treatment of HD.
