Abstract
Spinocerebellar ataxia (SCA-2) type-2 is a rare neurological disorder among the nine polyglutamine disorders, mainly caused by polyQ (CAG) trinucleotide repeats expansion within gene coding ataxin-2 protein. The expanded trinucleotide repeats within the ataxin-2 protein sequesters transcriptional cofactors i.e., CREB-binding protein (CBP), Ataxin-2 binding protein 1 (A2BP1) leading to a state of hypo-acetylation and transcriptional repression. Histone de-acetylases inhibitors (HDACi) have been reported to restore transcriptional balance through inhibition of class IIa HDAC's, that leads to an increased acetylation and transcription as demonstrated through in-vivo studies on mouse models of Huntington's. In this study, 61 di-aryl cyclo-propanehydroxamic acid derivatives were used for developing three dimensional (3D) QSAR and pharmacophore models. These models were then employed for screening and selection of anti-ataxia compounds. The chosen QSAR model was observed to be statistically robust with correlation coefficient (r2) value of 0.6774, cross-validated correlation coefficient (q2) of 0.6157 and co-relation coefficient for external test set (pred_r2) of 0.7570. A high F-test value of 77.7093 signified the robustness of the model. Two potential drug leads ZINC 00608101 (SEI) and ZINC 00329110 (ACI) were selected after a coalesce procedure of pharmacophore based screening using the pharmacophore model ADDRR.20 and structural analysis using molecular docking and dynamics simulations. The pharmacophore and the 3D-QSAR model generated were further validated for their screening and prediction ability using the enrichment factor (EF), goodness of hit (GH), and receiver operating characteristics (ROC) curve analysis. The compounds SEI and ACI exhibited a docking score of −10.097 and −9.182 kcal/mol, respectively. An evaluation of binding conformation of ligand-bound protein complexes was performed with MD simulations for a time period of 30 ns along with free energy binding calculations using the g_mmpbsa technique. Prediction of inhibitory activities of the two lead compounds SEI (7.53) and ACI (6.84) using the 3D-QSAR model reaffirmed their inhibitory characteristics as potential anti-ataxia compounds.
Highlights
Ataxia is a term indicating the lack of coordination and movement as a result of degeneration of cerebellum, the coordination center of brain
Data statistically demonstrated that the maxim of training set was greater than the maxim of test set and min of the training set was less than min of the test set, a condition which is prerequisite for a good QSAR model
Our study is guided with the ongoing effort toward the discovery and selection of the Hydroxamic based Histone de-acetylases inhibitors (HDACi) against ataxia
Summary
Ataxia is a term indicating the lack of coordination and movement as a result of degeneration of cerebellum, the coordination center of brain. Molecular pathology behind spinocerebellar ataxia type-2 (SCA-2) is the expansion of cytosine-adenine-guanine (CAG) repeat. Normal allele of SCA2 comprises of 13–37 repeats of CAG whereas the mutant allele comprises of 38–53 repeats (Armstrong et al, 2005). SCA2 is characterized through progressive gait and limb in-coordination, muscle weakness, slurring of speech, decreased vibration sense, and dysarthria. The onset of symptoms occurs in mid-40s and with the progression of diseased state, the patient is confined to wheel chair within a time span of 5–7 years. Till date there is no treatment available for SCA-2. Recent studies on SCA-2 have reported that the mutant protein having expanded trinucleotide (CAG) repeat sequesters the transcriptional factors affecting the expression of gene through transcriptional de-regulation (Brusco et al, 2004)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
