Molecular docking and dynamics simulation studies to identify the phytochemicals as lead molecules against the survival motor neuron 1 (SMN1) protein of spinal muscular atrophy

AbstractSpinal Muscular Atrophy is an autosomal recessive neuromuscular disorder resulting from deletions or mutations in the survival motor neuron (SMN1) gene. Loss of lower motor neurons (anterior horn cells) in the brainstem and spinal cord nuclei is a characteristic of SMA, which causes gradual symmetrical muscular weakening and atrophy. Currently, there are limited therapeutic options and there is an imminent medical need for new medications. This study focuses on the potential of phytochemicals derived from Brucea javanica and Tripterygium wilfordii as alternative agents for the treatment of SMA. Using molecular docking, a dataset of 115 phytochemicals from two plants was used to determine binding affinities with the SMN1 protein. 1000ns molecular dynamics (MD) simulation were performed on the high-binding affinities compounds to elucidate their stability and interaction dynamics in a physiological state. Yadanzioside-M and Triptersinine-A were two leading phytochemicals that developed sustained interactions with the SMN1 protein. Specifically, Yadanzioside-M formed hydrogen bonds with W92, S143, C146, D147, and finally D134 and S103. Its multi-cyclic structure exhibited pi-pi interactions with aromatic amino acids that enhanced the stability of protein-ligand. Likewise, Triptersinine-A established hydrogen bonds with R133, Y130, G129, and G131, as well as pi-pi interactions inside the Tudor domain’s aromatic cage, indicating a high binding affinity. These findings highlight the utility of the phytochemicals as neuroprotective agents with a prolonged bind to the target protein, suggesting that these are potential therapeutic agents for SMA. Further experimental and clinical research is needed to validate their efficacy and safety for therapeutic application.