Proteostasis and its relationship with autism: an in silico study

Abstract

Neurological diseases are a clear challenge to the world health system, and there is a growing need to thoroughly unravel the mechanisms involved in them. Autism Spectrum Disorder (ASD), for example, is a neurodevelopmental disorder, which, because it comprises a large spectrum of origin and evolution, is still a great challenge for researchers. Thus, the fact that it has a varied and poorly elucidated etiology, brings great difficulties in diagnosis, in besides the scarcity of treatments that provide significant improvements in the quality of life of patients with ASD. Throughout the centuries, the disorders linked to neurological conditions have always been treated differently because they differed exactly in their basic mechanism, origin, and evolution. However, recent research has been identifying several commonalities among them, which will certainly lead to progress in related studies, providing the development of faster diagnoses and more effective treatments. Dysregulation of proteostasis, for example, has been drawing attention, as it has been identified as a common feature in neurological diseases such as Autism, Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis. In the case of ASD, protein synthesis and maintenance are cited in several scientific papers, but little is known about the mechanisms behind its role in the disease. This paper, therefore, brings a study that aims to be thorough enough to determine the relationship of proteostasis, protein life, maintenance and death, and ASD. The main goal is to unravel the key mechanisms in protein control and maintenance in order to find potential targets to treat ASD. To this end, the paper provides a review of the most recent scientific topics that correlate autism to excitatory protein synthesis and suggests three target proteins linked to the process for further study. The eIF4E protein in specific, also called eukaryotic translation factor, was one of the targets mapped during the review study, the base material of all work. The scientific findings suggest that inhibiting the formation of the eIF4E- eIF4G initiation complex is a promising activity to treat some autism-related behaviors. To this end, the eIF4E protein was used as the target, and some in silico tests and studies were applied to it, in order to validate some scientific hypotheses, and find potential inhibitors of protein synthesis and its excitatory activity. The practice starts with a virtual screening search, based on the ligand already tested and validated as an inhibitor, found in several papers as an inhibitor of the protein in question, the 4EIG-1. After the selection of ligands with similar pharmacophore site, through the virtual screening process, tests of absorptivity, distribution, metabolism, excretion, toxicity, docking, and molecular dynamics were performed. At the end of the process, molecules are suggested that can start the research line of eukaryotic translation factor protein inhibitors. Besides being directed experimental tests with the best inhibitors, potentiating the possibility of these findings in the creation of a drug to treat ASD.