# Computational Search for Inhibitors of SOD1 Mutant Infectivity as Potential Therapeutics for ALS Disease

## TL;DR

This paper explores potential drugs to inhibit the spread of misfolded SOD1 proteins linked to ALS, using computational modeling and molecular docking.

## Contribution

The study introduces a computational approach to identify ligands that selectively bind to SOD1 mutant dimers, offering new therapeutic leads for ALS.

## Key findings

- Molecular dynamics simulations revealed structural differences in SOD1 mutant dimers compared to wild-type controls.
- Molecular docking identified ligands with higher affinity for mutant SOD1 dimers, suggesting potential therapeutic candidates.

## Abstract

Familial amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective degeneration of motor neurons. Among the main genetic causes of ALS, over 200 mutations have been identified in the Cu/Zn superoxide dismutase (SOD1) protein, a dimeric metalloenzyme essential for converting superoxides from cellular respiration into less toxic products. Point mutations in SOD1 monomers can induce protein misfolding, which spreads to wild-type monomers through a prion-like mechanism, leading to dysfunctions that contribute to the development of the disease. Understanding the structural and functional differences between the wild-type protein and its mutated variants, as well as developing drugs capable of inhibiting the propagation of misfolding, is crucial for identifying new therapeutic strategies. In this work, seven SOD1 mutations (A4V, G41D, G41S, D76V, G85R, G93A, and I104F) were selected, and three-dimensional models of SOD1 dimers composed of one wild-type monomer and one mutated monomer were generated, along with a control dimer consisting solely of wild-type monomers. Molecular dynamics simulations were conducted to investigate conformational differences between the dimers. Additionally, molecular docking was performed using a library of ligands to identify compounds with high affinity for the mutated dimers. The study reveals some differences in the mutated dimers following molecular dynamics simulations and in the docking of the selected ligands with the various dimers.