Computational Characterization of Trinucleotide Repeats (TNR) and Screening for Small Molecules and Polyphenols Targeting CAG and CCG Sequence Implicated in Neurological Disorders
Posted: 11 Feb 2020
Date Written: January 15, 2020
Trinucleotide repeats (TNRs) are present in human genes, with only few known functions. Nevertheless, the expansion in some repeats above the threshold limits results in more than 40 incurable neurological and neuromuscular disorders. It is well known that these expansions occur in both coding and non-coding regions of a number of genes. While CAG repeats are alone involved in most of the trinucleotide repeat expansion associated neurodegenerative disorders like Huntington’s disease (HD), different types of Spinocerebellar ataxia (SCAs), Spinal and bulbar muscular atrophy (SBMA) and Dentatorubral-pallidoluysian atrophy (DPLA). Recent evidences suggest that, the expansion of CAG repeats beyond the threshold limit causes these disorders and the repeat length is allied with the early onset and severity of the disease. Mutant CAG repeats are implicated in inducing cellular toxicity at both RNA and protein levels.
Hence trinucleotide repeats are considered to be promising drug targets in these diseases and can prove to be useful targets for RNA based small molecule therapy. While recent studies have made an effort using Anti-sense oligonucleotide therapeutic approaches, they have been confronted on the grounds of Blood-Brain barrier, poor absorption and allergic reactions. Therefore, our study focuses on understanding various types of TNR sequences, their loop/heteroduplex structural stability, features of expansion in normal, threshold and disease length, screening for new class of small molecules based on chemical similarity search to explore novel and various polyphenols like well-known Epigallocatechin gallate (EGCG) to target the pathogenic repeats via Virtual screening and docking analysis. Our extensive preliminary sequence and structural analysis outcome confirm motivating results like, occurrence number of CAG, GCG, CTG, CGG and GAA repeats their position, range, threshold of repeats and their effect of expansions in loop formation, structure and function in disease conditions. Similarly docking results confirmed that, chosen compounds bind selectively with better affinity across CAG and CCG repeats and ligand interactions with favorable binding energies. Further, in silico results will be evaluated by different biophysical methods like CD, UV melting and ITC. Thus our results indicate that the use of screened small molecules is far more favorable and efficient therapeutic approach overcoming limitations as well.
Keywords: Trinucleotide repeats (TNRs), Neurological disorders, Neuromuscular disorder, Virtual screening and docking, Polyphenols
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