Elucidation of Pharmacological Mechanism Underlying the Anti-Alzheimer's Disease Effects of and Discovery of Novel Lead Molecules: An In Silico Study.

Alzheimer's disease (AD) is a brain disease with a peculiarity of multiformity and an insidious onset. Multiple-target drugs, especially Chinese traditional medicine, have achieved a measure of success in AD treatment. (Juss.) Benth. (Wuzhuyu, WZY, i.e., ), a traditional Chinese herb, has been identified as an effective drug to cure migraines. To our surprise, our in silico study showed that rather than migraines, Alzheimer's disease was the primary disease to which the active compounds were targeted. Correspondingly, a behavioral experiment showed that extract could improve impairments in learning and memory in AD model mice. However, the mechanism underlying the way that compounds target AD is still not clear. For this purpose, we employed methods of pharmacology networking and molecular docking to explore this mechanism. We found that showed significant AD-targeting characteristics, and alkaloids of played the main role in binding to the key nodes of AD. Our research detected that affects the pathologic development of AD through the serotonergic synapse signaling pathway (SLC6A4), hormones (PTGS2, ESR1, AR), anti-neuroinflammation (SRC, TNF, NOS3), transcription regulation (NR3C1), and molecular chaperones (HSP90AA1), especially in the key nodes of PTGS2, AR, SLCA64, and SRC. Graveoline, 5-methoxy-N, N-dimethyltryptamine, dehydroevodiamine, and goshuyuamide II in show stronger binding affinities to these key proteins than currently known preclinical and clinical drugs, showing a great potential to be developed as lead molecules for treating AD.