In Silico Evaluation of Guanfacine Interactions with ALS-Associated Neuroimmune Proteins: Structural and Molecular Dynamics Analysis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is linked to multiple neuroimmune and inflammatory alterations, where further identification of additional molecular targets and candidate molecules is important. Guanfacine is a selective central α₂A-adrenergic receptor agonist, already used in various clinical applications, as well as a molecule showing interesting properties due to its influence on glial cells and inflammatory processes. Due to the fact that dysregulation of neuroimmune signaling is related to the pathological mechanisms of ALS, the current study utilizes an integrative computational approach to investigate the potential interactions between Guanfacine and four neuroimmune-associated proteins: RAGE (AGER), Toll-like receptor 4 (TLR4), chitinase-3-like protein 1 (CHI3L1), and interleukin-13 receptor α2 (IL-13Rα2). The molecular docking was conducted for comparing the binding of Guanfacine to these proteins, and then the 100-ns molecular dynamics simulation was conducted for investigating the RAGE-Guanfacine complex. Guanfacine showed docking scores of -7.47, -6.65, -5.21, and -4.28 kcal/mol against RAGE, CHI3L1, TLR4, and IL-13, respectively, and the most promising interaction was shown by RAGE. During the molecular dynamics simulation, the RAGE-Guanfacine complex stayed bound in the studied region, and multiple hydrogen bonds, water bridges, and hydrophobic interactions occurred. This evidence suggests a structure-based rationale for selecting RAGE to conduct future investigations of the interaction between Guanfacine and its neuroinflammatory role in ALS. However, the results obtained from the computational analysis are not sufficient to prove binding affinity, modulation, anti-inflammatory, and neuroprotective effects of Guanfacine. Thus, the paper presents a hypothesis that needs to be proven.