Abstract
Purpose: To design dual inhibitors against Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) via pharmacoinformatics approach.
Methods: Dual Drug Candidates (DDC) were designed and explored for their molecular interaction with several AD and T2DM targets. Pterostilbene, a natural anti-T2DM compound was coupled with different cholinesterase inhibitors to design DDC. Orisis Datawarrior online property calculator tools, Autock 4.2 and Hex 5.1 were used to investigate the potency of all DDC relative to positive controls.
Results: The study found that DDC2 (pterostilbene - methylene linker -octa hydro amino phenothiazine), DDC3 (pterostilbene - ethylene linker - N-phthalimide) and DDC5 (pterostilbene carbonyl linker - 2-methyl-4-aminoquinoline) were the most promising out of all the DDCs. DDC2 showed strong molecular interaction with most of the AD and T2DM targets, including acetylcholinesterase, butrylcholinesterase, beta-secretase, receptor for advanced glycation end products and ATP sensitive potassium channel, dipeptidyl peptidase IV and sodium glucose transport protien 2. The findings also revealed the amyloid anti-aggregation potential of DDC.
Conclusion: The results show that DDC3 and DDC5 significantly interfer with the primary nucleation process of beta amyloid. Thus, DDC2, DDC3 and DDC5 have strong anti-T2DM and anti-AD potential.