Multi-targeted Virtual Screening of Phytocompounds of Rauwolfia serpentina Against Caspase-8, BACE, and AChE for the Treatment of Neurodegenerative Diseases

Abstract

Brain-related disorders that are associated with neurodegeneration are collectively termed neurodegenerative disorders (NDs). They pose a serious concern for human health, especially among older people. Nearly 47 million individuals are living with dementia; this is expected to increase three times by 2050. The blood–brain barrier is considered a major challenge in the development of drugs against NDs. Rauwolfia serpentina is a medicinal plant traditionally used for the treatment of NDs such as schizophrenia, anxiety, insomnia, and mental illness. In this study, the compounds of this plant were examined against caspase-8, β-secretase, and acetylcholinesterase of NDs. The detailed toxicological profile, adsorption, distribution, metabolism, excretion (ADME) properties, and pharmacokinetics were predicted, followed by virtual screening with molecular docking. Based on the toxicity, drug likeliness, pharmacokinetics, anti-neurodegenerative activity, binding site in target proteins, and binding energy, alstonine and rauwolscine were identified as lead compounds. The molecular dynamics simulation of lead compounds was also performed to study their dynamics and stability by mimicking the physiological conditions. Only three compounds showed Ames toxicity, and none of the compounds were predicted to be human Ether-à-go-go-Related Gene (hERG) I inhibitors or cause oral rat acute toxicity. Alstonine was predicted to be active against Alzheimer’s disease and neurodegenerative diseases, and rauwolscine was predicted to be active against acute neurologic disorders. The energies for interaction of alstonine and rauwolscine were −10.1 and −8.7 kcal/mol, respectively. Molecular simulation analysis confirmed the stable nature of both the ligands with all three target proteins under physiological conditions. The data of this study highlight the potency of alstonine and rauwolscine for the treatment of NDs, and these compounds could be developed as effective drugs after careful in vivo examination.