Avaliação in silico de alcaloides B-carbolínicos como potenciais inibidores da acetilcolinesterase

Abstract

Alzheimer's disease is a progressive neurodegenerative disease that affects millions of elderly people worldwide and is the most common form of dementia. The cholinergic hypothesis is based on the decrease in the synthesis of the neurotransmitter acetylcholine, compromising the cholinergic function. Thus, a therapeutic strategy adopted for this hypothesis is the use of drugs that act in the inhibition of acetylcholinesterase, increasing levels of acetylcholine, and favoring neurotransmission. The present work aims to study β-carbolinic alkaloids as acetylcholinesterase inhibitors through molecular docking studies and analysis of their pharmacokinetic properties. To this end, 92 alkaloids from 14 different subclasses were analyzed. Among them, the alkaloid penipalin B showed essential interactions with the peripheral anionic subsite of AChE, evidenced by docking studies, being observed the interactions with residues TYR337 and TRP286, already described in the literature as being important for the inhibition of this enzyme. Additionally, it scored higher than the drugs galantamine, physostigmine, and huperzine A, indicating that this alkaloid has a relevant affinity with the enzyme. The pharmacokinetic study evidenced important characteristics for its action as a drug, possessing a high probability of being permeable by the blood-brain barrier and easily absorbed by the gastrointestinal tract, which is desirable for drugs that act as AChE inhibitors. Furthermore, penipalin B was not shown to be an inhibitor of CYP enzymes. Regarding toxicity predictors such as the low risk of hERG inhibition and a negative result for carcinogenicity in rats and mice were also observed for this alkaloid. Therefore, according to the data obtained, penipalin B becomes the most promising inhibitor among the ligands studied due to its essential interactions with important residues of AChE and its pharmacokinetic properties