Busca de pequenas moléculas naturais inibidoras da Rab10 para o tratamento da doença de Alzheimer

Abstract

Alzheimer's disease (AD) is a neurodegenerative, polygenic and multifactorial disorder associated with aging. Despite advances in investments, so far there is no effective treatment for this dementia. Various enzymatic targets have been and are still being studied in an attempt to discover new drugs for the treatment of AD; however, Rab GTPases are still relatively unexplored. These enzymes regulate cellular processes by alternating of GDP and GTP nucleotides. Studies have shown that the knockdown of Rab10 reduces the production of Aβ42 peptides in the brain parenchyma, making it a promising target for the treatment of AD. In order to identify potential Rab10 inhibitors, the structure-based virtual screening (SBVS) technique was used considering a subset of 80763 natural compounds of ZINC15 database. Tertiary structure of Rab10 was obtained from the Protein Data Bank (PDB) and the Autodock Vina program was used in the SBVS, carried out in three sequential steps to filter potential bioactive substances against this enzyme. The SBVS protocol was validated by redocking the co-crystallized GNP nucleotide and the binding energies of the GDP and GTP nucleotides were used as controls in the pharmacodynamic analysis. Thus, it was possible to select 45 compounds with binding energy less or equal -11 Kcal.mol -1 . Absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties of these compounds were evaluated by the SwissADME program, where it was possible to identify 6 promising molecules. The resulting complexes were subjected to molecular dynamics simulations to analyze the pharmacodynamics over time. The results suggest that the compound ZINC4090657 (derived from quinolizidine) and the compounds ZINC4000106 and ZINC0630250 (derived from coumarin) have favorable pharmacological characteristics for the inhibition of Rab10, with ZINC4090657 being the most promising one.