Avaliação por bioquímica quântica de interações entre o receptor beta secretase 1 (BACE1) e Ligantes

Abstract

Alzheimer's disease (AD) is a progressive multifactorial neurodegenerative disorder and the main cause of dementia in late adulthood. The amyloid cascade hypothesis suggests a deposition of beta amyloid (Aβ) in the brain, as a result, there is an imbalance between the production and clearance of the Aβ peptide deposited in diffuse plaques. This is the cause of damage in AD. In recent years, several drugs have been developed to reduce the concentrations of Aβ40 and Aβ42, including 4-Butoxy-3-chlorobenzyl imidothiocarbamate and Verubecestat, which have a great potential to minimize the production of the peptide. This work analyzes the main interactions that occur between a Beta secretase 1 (BACE1) and its ligands using the Molecular Fragmentation Method with Conjugated Caps (MFCC), using the DFT (Density Functional Theory) approach for identification of which amino acid residues contribute to the binding between the drugs, mentioned before, and receptor. The results showed the energetic values of each amino acid residue constituting the site of interaction with the ligands under analysis. This assessment took place within a radius of up to 10.0 Å away from the drugs. The results show that 4- Butoxy-3-chlorobenzyl imidothiocarbamate has greater affinity to the molecular target than Verubecestat. Residues ASP93, ASP289, TYR132, SER96, THR293, GLY291, LEU91, ILE179, THR292, TRP176, GLY95, PHE169, GLN134 are important for system formation with the two drugs. Of these, the ASP93 and ASP289 are key pieces for stabilizing the formation of complexes. The data found are essential for creating new strategies in the development of drugs that can contribute to improving the quality of life of patients with AD.