Curcumin Analogues as Promissory Compounds for Inhibition of β-Secretase, γ-Secretase and GSK-3β Implicated at Alzheimer Disease: In Silico Study

Abstract

Aims: Alzheimer's disease is a disorder associated to dementia that widely affects to population. In the molecular study, key enzymes have been associated with the regulation of the amyloid pathway, which have a focus in the discovery of possible inhibitors. Likewise, the absence of specific treatments, has promoted the development of promising molecules from natural sources. Material and Methods: In this study was carried out an in-silico exploration of curcumin analogues against β-secretase, γ-secretase and GSK-3β. A virtual screening of 373 curcumin analogues against enzymes implicated in the pathology was implemented, using molecular docking simulations through Autodock-Vina based on PyRx 0.8. Followed by in-silico prediction of ADMET properties to molecules with higher affinity using SwissADME and GUSAR prediction. Results: It was obtained that the molecules of highest affinity were 92296662, 102584924, 92341226 for β-secretase, γ-secretase and GSK-3β, respectively. These were contrasted with selective inhibitors for enzymatic systems. Additionally, the predictions of the ADMET properties of the analogues showed a variability in terms of metabolism, non-permeation on blood–brain barrier and toxicity values ​​according to reported in the literature. Thus, in-silico prediction indicated curcumin analogues as possible regulatory agents of the enzymatic activity associated to Alzheimer's disease.