ADMET Profiling and In-silico Screening of Himalayan Phytoconstituents as Multi-Targeting Alzheimer's Disease Inhibitors: A Reverse Pharmacology Method.

Alzheimer's disease (AD) is a neurodegenerative disorder caused by multiple factors that require the development of multi-target directed ligands (MTDL) to treat its pathophysiology. Using Hyperoside, a major Himalayan plant extract, this study will report on the potential use of this compound as a therapeutic agent for treating the main amyloidogenetic (amyloid precursor protein) and neurochemical (toxic metabolism of neurotransmitters) drivers of the progression of AD through reverse pharmacology and molecular modeling (in silico) docking studies. Hyperoside was identified as a potential inhibitor of BACE1 (1FKN) and MAO-B (2V5Z) through the use of in silico molecular docking studies, with reported binding affinities of -8.8 and -8.2 kcal/mol, respectively. Additionally, Hyperoside exhibited significant inhibitory potential against both beta-amyloid production and oxidative neurotransmitter degradation. To evaluate the drug-like properties and potential for pharmacokinetic use of Hyperoside as a potential treatment for AD, the lead compound underwent extensive ADMET profiling. The BOILED-Egg model (SwissADME) indicated Hyperoside had good gastrointestinal absorption and was not predicted to passively cross the blood-brain barrier (BBB) because of the compound's high Topological Polar Surface Area (TPSA = ~191 Å^2). In addition, molecular docking studies performed on the lead compound for its interaction with Human Serum Albumin (HSA) protein (1AO6) provided a docking score of -8.0 kcal/mol, indicating systemic transport via blood proteins is likely. These results indicate that the use of Hyperoside as an MTDL may provide a strong starting point for the development of a multi-targeted lead scaffold for the treatment of AD; however, in order for Hyperoside to be an effective treatment in the central nervous system, additional work may be needed to improve the delivery of Hyperoside into the CNS using nanocarrier techniques. The research presented here provides a comprehensive computational basis for confirming that Himalayan Traditional Medicine possesses qualities that may translate into the development of new treatment options for Alzheimer's disease.