Molecular Modeling Strategies for the Therapeutic Intervention of Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME)

Abstract

SMA-PME has been recognized as a rare autosomal recessive neuromuscular disorder. It is depicted as a childhood onset of proximal muscular atrophy progressive with myoclonic seizures. This disorder is caused by 13 SNP mutations in the ASAH1 gene, which encodes acid ceramidase (aCDase) proenzyme. After activation aCDase hydrolyzes lysosomal ceramide into sphingosine and fatty acid, thus maintains lipid’s cellular homeostasis. As a result of mutations, transcription of premature proenzyme occurs, which leads to activity loss of aCDase up to the one-third level. Therefore, due to enzyme insufficiency, there is ceramide accumulation and neural cell degradation such as SMA-PME. Until now, no cure for aCDase deficiency has been recognized, and the standard of treatment focuses on symptom management. However, recent proof of study on structural activation of aCDase has proposed as a source of recombinant therapy of Farber Disease. It shows that the catalytic domain of the aCDase can perform work when combined with some potent peptide (tag). Moreover, research on the ASAH1 gene with biological regulatory pathways investigations highlights the role of transcription factors (CREB) in inducing gene expression.

In present study, two therapeutic options have been explored:1. r-aCDase modeling- by optimizing the stability between the binding domain of aCDase and a tag peptide

for. 2.ASAH1 driven signaling pathway to induce the expression of TF (CREB) to

enhance the production of aCDase. This research resulted into the three stable r- aCDase structures that can be used to improve the transport and efficacy of aCDase.

Furthermore, it was also identified that most significant residue for CREB induction was ARG131, SEP133, TYR134 and ILE137. Most probable 3D binding conformation of the template after MD simulation was used for 3D predictive modeling. The built pharmacophore model exhibited 92% accuracy with two H-bond acceptors and two hydrophobic features. Lastly, an integrated virtual screening pipeline was generated to predict 19 FDA approved drugs as potential hits against CREB to induce ASAH1 gene expression. Thus, the proposed hits can be utilized in future for further experimental validation.