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Spinocerebellar Degeneration is a neurological disorder of central nervous system (CNS) mainly occurs due to cerebellum degeneration, the brain’s coordination centre. Spinocerebellar ataxia (SCA) as referred in medical terminology; it’s phenotype include in-coordination, slurring of speech, slow reflexes, saccadic eye movements, motor disturbances with the patient confining to wheel chair and eventually to bed in 6-7 years from the first appearance of the symptoms. Molecular physiology trailing spinocerebellar ataxia (SCA’s) is the expansion of cysteine-adenine-glutamine (CAG) trinucleotide repeats within the coding region of ataxin (ATXN) gene. Expanded polyglutamine repeat sequesters transcriptional co-activators (CBP, A2BP1, p300, TDP-43, DDX-6 & PABPC1), responsible for the histone acetylation, thereby de-regulating transcription. Under, normal physiological condition there is a balance between protein acetylation and de-acetylation amid transcription through HAT and HDAC’s. Sequestration of the transcriptional co-activators results in the state of hypo-acetylation which can be reversed through inhibiting HDAC’s. Thereby, HDAC inhibitors act as one of the major therapeutics towards poly-glutamine disorders including SCA’s. In-vitro studies have also demonstrated that HDAC inhibitors arrest the neuronal degeneration induced by poly-glutamine (CAG) expanded repeats. In our research we have identified the deleterious nsSNPs in SCA2 condition utilizing the algorithms viz. SIFT, Polyphen 2.0, PANTHER, I-mutant 2.0, Phd-SNP, Pmut, MutPred. Further, molecular dynamics simulations and structural analysis were performed to observe the brunt of disease associated nsSNPs toward the strength and secondary properties of ataxin-2 protein structure. In conjugation with protein inhibitor interaction study we have also analyzed the structural changes anticipated through computationally predicted mutations using MD simulations to determine the changes on its time dependent physiological affinities and biochemical pathway alterations within the ataxin-2 protein. A total of 105 HDAC inhibitors having hydroxamic moeity were selected, using G-QSAR, 3D-QSAR model and pharmacophore hypothesis model that co-relate the biological and physiochemical properties of the molecules against class IIa HDACs. We have applied a combined prediction as well as screening methodology i.e., to identify the structural based modifications required for hydroxamate derivatives as anti-HDAC compounds through G-QSAR model based prediction as well as a combined screening methodology along with prediction of inhibitory potential of the molecules using 3D-QSAR model. The potential leads retrieved from both the approaches were validated by elucidating their binding pattern with class IIa HDAC (HDAC4) employing molecular docking and dynamics simulations. The selected lead having the highest predicted activity was synthesized and evaluated against human neuronal cell line (IMR-32). The synthesized molecule (HIC) down regulated the HDAC4 enzyme at 40 (μ) micro molar concentration.
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