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Highlights Drug repurposing of FDA approved drugs from ZINC 12 database was done using the crystal structure of extracellular domain of human NEP (PDB ID: 5JMY ) The interactions with catalytic triad of HIS583, HIS587 and GLU646 are important for NEP inhibition. Based on XP molecular docking, binding energy, IFD-SP and MD simulation top 4 NEP inhibitors were identified. ZINC000000601283 and ZINC000003831594 were found to be stable during MD simulation and may act as NEP inhibitors.

Wnt signaling pathway is an evolutionarily conserved pathway responsible for neurogenesis, axon outgrowth, neuronal polarity, synapse formation, and maintenance. Downregulation of Wnt signaling has been found in patients with Alzheimer’s disease (AD). Several experimental approaches to activate Wnt signaling pathway have proven to be beneficial in alleviating AD, which is one of the new therapeutic approaches for AD. The current study focuses on the computational structure-based virtual screening followed by the identification of potential phytomolecules targeting different markers of Wnt signaling like WIF1, DKK1, LRP6, GSK-3β, and acetylcholine esterase. Initially, screening of 1924 compounds from the plant-based library of Zinc database was done for the selected five proteins using docking approach followed by MM-GBSA calculations. The top five hit molecules were identified for each protein. Based on docking score, and binding interactions, the top two hit molecules for each protein were selected as promising molecules for the molecular dynamic (MD) simulation study with the five proteins. Therefore, from this in silico based study, we report that Mangiferin could be a potential molecule targeting Wnt signaling pathway modulating the LRP6 activity, Baicalin for AChE activity, Chebulic acid for DKK1, ZINC103539689 for WIF1, and Morin for GSk-3β protein. However, further validation of the activity is warranted based on in vivo and in vitro experiments for better understanding and strong claim. This study provides an in silico approach for the identification of modulators of the Wnt signaling pathway as a new therapeutic approach for AD. Graphical Abstract

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Purpose: Alzheimer's is a disease affecting mostly the Older population leading to the deterioration of cognitive capabilities. The protective effect of Caffeic acid in Colchicineinduced dementia was evaluated in the current study. Materials and Methods: Colchicine was administered intracerebroventricularly (ICV) to the lateral ventricle of the brain (at the coordinates 0.8 mm posterior to bregma, 1.8 mm lateral to the sagittal suture, 3.6 mm below the cortical surface) using robotic stereotaxic apparatus that results in Alzheimer's type sporadic dementia. Caffeic acid at the dose of 50 mg/kg p.o, was administered daily for 25 days starting four days before the colchicine injection and evaluated for its neuroprotective activity. The spatial memory of animals was evaluated using Morris water maze followed by biochemical estimations of acetylcholinesterase and antioxidant markers in the hippocampal and frontal cortex region of the brain. Results: Intracerebroventricular injection of colchicine in rat brain resulted in decreased cognitive abilities as evident in escape latency and average speed of the retention trial. Significant changes in the escape latency were noted in Caffeic acid-treated group. The level of acetylcholinesterase and antioxidant markers like glutathione, catalase, lipid peroxidation, superoxide dismutase were significantly changed in the hippocampal region of the rats but not in the frontal cortex region in the caffeic acid treatment groups. Conclusion: The current study provides evidence for the neuroprotective and antioxidative potential of caffeic acid in intracerebroventricularly injected Colchicine-induced sporadic model of AD.