Multitarget evaluation of molecules from marine animals against Alzheimer's disease, related to gamma‐ and beta‐secretases and cathepsin B protein targets

Abstract

AbstractBackgroundOne of the causes for Alzheimer’s disease (AD) is the secretase activity on the APP protein, producing ß‐amyloid peptides (Aß) that aggregate and accumulate in regions of the brain, causing cell death (WAKABAYASHI; STROOPER, 2008). Secretase (β and γ) inhibitors have been studied as an alternative to treatment, but they have exhibited toxicity or ineffectiveness; however, these enzymes are still considered potentially effective therapeutic targets. Besides these inhibitors, cathepsin B is considered another possible inhibitory target for its involvement in protein clearance and neuroinflammation (CHITRANSHI et al, 2021). Thus, this work aimed to analyze, by virtual screening, the inhibition of such enzymes, among molecules described from marine animals, in order to obtain a new prototype for amyloid plaques decrease.MethodMolecules from marine animals were searched in scientific articles and prepared for docking, conducted by Swiss Dock server, to predict molecular interaction with β and γ‐secretases and cathepsin B (selected on PDB). Results were analyzed by UCSF Chimera and, by predicting the molecular interaction, the molecules were selected if they were positioned in the enzyme active site, with distance lower than 3 Å and binding energy lower than ‐5 kcal/mol.ResultAmong 50 molecules, Sebastianine A obtained a positioning exactly in the active site of the β‐secretase, presenting favorable binding energy of ‐6.74 kcal/mol and the binding distance of 2.395 Å with the amino acid Thr72. Regarding the γ‐secretase, it was observed the lowest binding energy of ‐6.86 kcal/mol, and 2.42 Å to the amino acid Lys380. Lastly, in the case of cathepsin B, it was possible to identify a distance of 3.091 Å and binding energy ‐6.45 kcal/mol to the amino acid Gln25.ConclusionSebastianine A has the potential to inhibit 3 important enzymes for the AD development, in a multitarget approach, relevant for this complex disease. This result represents a promising drug candidate for this disease without cure so far.