Exploring Aromatic Medicinal Compounds for the Treatment of Amyotrophic Lateral Sclerosis

Abstract

Purpose: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative condition, in which motor neurons start to degenerate due to the accumulation of protein aggregates in the neuron cytoplasm. The formation of aggregates causes neurotoxicity, facilitated by the N-terminal domain (NTD) of the transactive response DNA-binding protein-43 (TDP-43). Therapies used to treat ALS manage secondary symptoms, but do not stop the activity of the rogue NTD domain of TDP-43. Therefore, new drug candidates should be designed to deal efficiently with this disease by inhibiting the domains involved in the development of ALS. This study determined the chemical affinity of aromatic medicinal compounds with NTD. Screening of 1323 medicinal compounds was conducted with PYRX 0.9 software against NTD. Compounds obtained from this analysis were further used to predict absorption, distribution, metabolism, excretion, and toxic (ADMET) properties and their effect on major gene targets of ALS. Results: From 1300 + compounds, acetovanillone showed binding affinity for NTD and had good ADMET and drug likeness attributes. This compound reduced the expression of CXCL2, NOP56, and SOD1 genes implicated in ALS pathogenesis. Conclusion: These results concluded that acetovanillone is a candidate drug for in vitro and clinical studies into the exploitation of drugs within ALS therapeutics.