In Silico Design of Acetylcholinesterase and Glycogen Synthase Kinase-3β Multi-target Inhibitors

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by multifactorial processes related to different biological targets. Acetylcholinesterase (AChE) inhibitors have been used in AD treatment, but other therapeutic alternatives have prospected, such as Glycogen Synthase Kinase-3β (GSK-3β) inhibitors. Considering the limitations of one-target drugs, the use of multi-target directed drugs rises as a promising strategy. Design new AChE-GSK-3β dual inhibitors as propitious multi-target drug candidates for AD treatment. Thirteen natural products were selected, molecular docking, molecular dynamics, pharmacophore modeling, ADME/Tox predictions and proposals development was performed. Given the results obtained and considering structural subunits of AChE and GSK-3β inhibitors, structural modifications were done to design new hybrids proposals. Hydrophobic and hydrogen bond interactions between compounds and important residues of AChE and GSK-3β were observed, besides, three pharmacophoric features were founded: one aromatic ring and two hydrogen bond acceptors. Compounds also demonstrated favorable ADME/Tox predictions. Subsequently, these results afforded the use of physostigmine and luteolin as prototypes for the design of nine hybrid proposals: five AChE inhibitors and four AChE-GSK-3β dual-inhibitors. Their bioactivity prediction showed that all proposals should exhibit anti-Alzheimer related activity; ADME/Tox predictions showed best results for Proposals 1, 2 and 5; and Proposals 6, 7, 8 and 9 presented higher affinity for both AChE and GSK-3β enzymes. Proposals 1 and 2 were considered potential AChE inhibitors, and Proposals 6 and 8 were elected as potential AChE-GSK-3β dual inhibitors for therapeutics in AD.