ArticleScientific reports2024
In-Silico discovery of 17alpha-hydroxywithanolide-D as potential neuroprotective allosteric modulator of NMDA receptor targeting Alzheimer's disease.
Article in Scientific reports, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed.
- Review
- Exploring the Analgesic Potential of L-Lysine: Molecular Mechanisms, Preclinical Evidence, and Implications for Pharmaceutical Pain Therapy.Pharmaceutics · 2025Review
- Role of Saponins fromMolecules (Basel, Switzerland) · 2025Article
- Resveratrol attenuates pulmonary fibrosis by inhibiting alveolar epithelial senescence via targeting SASP-related proteins: an integrated bioinformatics-experimental study.Frontiers in pharmacology · 2025Article
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6 authors.
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Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory impairment, and behavioral alterations. The N-methyl-D-aspartate (NMDA) receptor has emerged as a promising target for AD pharmacotherapy due to its role in the disease's pathogenesis. This study leverages advanced computational methods to screen 80 active constituents of Withania somnifera (Ashwagandha), a traditional herb known for its neuroprotective effects, against the NMDA receptor, using FDA-approved Ifenprodil as a reference. Our blind virtual screening results demonstrated that all tested compounds could bind to various domains of the NMDA receptor, with binding energies ranging from - 4.1 to -11.9 kcal/mol, compared to Ifenprodil's -7.8 kcal/mol. Binding preference analysis revealed 7 compounds bound to the A-chain, 37 to the B-chain, 7 to the C-chain, and 29 to the D-chain of the receptor. Notable binding was observed predominantly at the Amino Terminal Domain (ATD) core site, some at the ATD-Ligand Binding Domain (LBD) interface, and a few at the Transmembrane Domain (TMD). Particularly, 17alpha-hydroxywithanolide D, with a binding energy of -11.9 kcal/mol, emerged as a prime candidate for further investigation. Molecular dynamics simulations of this compound revealed key interactions, including direct hydrogen bonding with residues ASP165, ARG431, THR433, LYS466, and TYR476 on the D-chain, as well as additional hydrophobic and water-bridging interactions. These simulations highlighted the compound's influence on dynamic conformational states of the GluN1b-GluN2B receptor complex, modulating interactions between GluN1b Lys178 and GluN2B Asn184. Furthermore, the compound affected the distance between LBD heterodimers and the tension within the LBD-M30 linker, demonstrating its potential to modulate NMDA receptor activity. This comprehensive study not only underscores the therapeutic promise of Withania somnifera derivatives for AD but also provides a detailed molecular basis for their efficacy, offering valuable insights for targeted drug development and innovative therapeutic strategies against Alzheimer's disease.
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