Comprehensive profiling of traditional herbomineral formulation Manasamitra vatakam in rat brain following oral administration and in-silico screening of the identified compound for anti-Alzheimer's activity.

Multi-targeted drug therapy has received substantial attention for the treatment of diseases of multifactorial origin, such as neurodegenerative diseases. Manasamitra vatakam (MMV) is a traditional Ayurvedic formulation used to improve cognitive impairment and mental illness. Here we have used a unique method for leveraging the barrier properties of the intestinal and blood-brain barrier (BBB) to screen and identify the bioactive molecules against Alzheimer's disease (AD). The current method exemplifies a facile method to expedite drug discovery from traditional formulations. The present study aimed to identify the phytoconstituents of MMV that reach the brain tissue and to predict major bioactive constituents by computational docking studies. After oral administration of the formulation, brain samples from male Sprague Dawley rats were collected at different time intervals and analyzed by liquid chromatography-mass spectrometry (LC-MS) to identify the phytoconstituents. In silico molecular docking studies were carried out to analyze the binding affinity of the compounds to the target proteins of AD using Schrodinger Maestro. The molecular dynamic studies were carried out for all the docked complexes having higher docking scores. 34 phytoconstituents were identified by LC-MS analysis of brain homogenates. In the in silico docking study, the phytoconstituents chrysin, convolvin, rutin, galangin, palmatoside G, isoliquiritigenin, quercetin, and naringenin showed higher docking score against the target proteins of AD. These compounds may serve as the primary bioactive compounds responsible for the neuroprotective activity of the herbal formulation. Furthermore, molecular dynamic studies indicated that the galangin-acetylcholinesterase enzyme complex has the highest stability among these eight compounds. The study, together with previous in vivo and in vitro efficacy results, suggests that BBB-permeable compounds with high binding affinities for the target proteins of AD might be responsible for the effectiveness of MMV against AD. [Display omitted] • An effective approach to expedite the drug discovery from traditional formulations. • After administration of the formulation, 34 compounds were identified in rat brain. • Eight compounds showed dual-inhibitory properties towards both AChE and BACE1. • Galangin-Ach E complex showed most stability, in molecular dynamic studies. [ABSTRACT FROM AUTHOR]

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