Benzo[b]thiophene-based bis-ureas as inhibitors of Aβ-LilrB2 aggregates in Alzheimer’s Disease: an in silico investigation

• Autor(a) principal: Santos, Joel José Pereira
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/39541
• topic: Alzheimer’s Disease; Drug discovery; Aβ Aggregates-LilrB2; Benzo[b]thiophenebased Bis-ureas; Molecular dynamics; Free energy calculations

Alzheimer’s Disease (AD) is a chronic neurodegenerative disease with high socioeconomic costs. Due to its complexity, existing therapies only alleviate symptoms and/or delay its progression. The formation of Amyloid β (Aβ) protein aggregates resulting from the breakdown of Aβ precursor protein (APP) has been identified as one of the factors responsible for the onset and development of AD. The accumulation of Aβ aggregates in the brain leads to neuronal cell death due to the diffusion of oligomers (AβOs). AβOs act through multiple mechanisms by interacting with receptors located on the cell surface. One of these receptors, with high affinity for AβOs, is the Leukocyte Immunoglobulin-Like Receptor B2 (LilrB2), expressed in the cerebral microglia. The association of AβOs with LilrB2 and with the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) impairs the immune response to the diffusion of Aβ aggregates, leading to loss of synaptic plasticity and the memory deficits that characterize AD. Therefore, the inhibition of LilrB2 by supramolecular association with drug-like molecules emerges as a possible treatment of this pathology. In this context, the present dissertation presents an investigation at the molecular level of the interaction of AβOs with LilrB2 and with two sets of ligands. These studies were carried out using docking methods, followed by molecular dynamics (MD) simulations and free energy calculations using Molecular Mechanics/Generalized Born Surface Area (MM/GBSA). The first set of molecules (A) consists of six drugs with diverse structures and different affinities for LilrB2, as demonstrated in one experimental study reported in the literature. The second set of molecules (B) is composed of ten bis-ureas obtained by coupling ortho-phenylenediamine with two benzo[b]thiophenes through the Cα, Cβ, or Cy carbons of this heterocyclic ring. The B-series comprises structural isomers with different shapes, varied lipophilic character, and different putative affinities for the amino acids in the binding groove of LilrB2, determined by different degrees of fluorination. The α derivatives, with extended structures, show higher affinity for the hydrophobic cavity of LilrB2, even when compared to the molecules in set A, due to hydrogen bonding coupled with hydrophobic interactions with amino acids Asp36, Val38, Val114, and Pro164 of the cavity. This computational study indicated a potential repositioning for the molecules in the B-series, initially designed and developed for transmembrane transport of anions in the context of channel replacement therapies in diseases such as Cystic Fibrosis (CF).