In-Silico discovery of 17alpha-hydroxywithanolide-D as potential neuroprotective allosteric modulator of NMDA receptor targeting Alzheimer’s disease
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. T...
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Nature Portfolio
2024-11-01
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| Online Access: | https://doi.org/10.1038/s41598-024-78975-2 |
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| author | Manoj Kumar Vashisth Junkai Hu Mingrui Liu Syed Hussain Basha Chen Yu Wenhua Huang |
| author_facet | Manoj Kumar Vashisth Junkai Hu Mingrui Liu Syed Hussain Basha Chen Yu Wenhua Huang |
| author_sort | Manoj Kumar Vashisth |
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| description | 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. |
| format | Article |
| id | doaj-art-a7a1ee3893954c358e70346b0149d0b0 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-a7a1ee3893954c358e70346b0149d0b02024-11-17T12:27:25ZengNature PortfolioScientific Reports2045-23222024-11-0114111910.1038/s41598-024-78975-2In-Silico discovery of 17alpha-hydroxywithanolide-D as potential neuroprotective allosteric modulator of NMDA receptor targeting Alzheimer’s diseaseManoj Kumar Vashisth0Junkai Hu1Mingrui Liu2Syed Hussain Basha3Chen Yu4Wenhua Huang5Department of Human Anatomy, School of Basic Medicine Sciences, Southern Medical UniversityDepartment of Orthopaedics, Affiliated Hospital of Guangdong Medical UniversityDepartment of Human Anatomy, School of Basic Medicine Sciences, Dali UniversityInnovative Informatica TechnologiesCentral Laboratory, Affiliated Hospital of Putian University, Putian UniversityDepartment of Human Anatomy, School of Basic Medicine Sciences, Southern Medical UniversityAbstract 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.https://doi.org/10.1038/s41598-024-78975-2Alzheimer’s diseaseN-methyl-D-aspartate receptorWithania somniferaVirtual screeningDockingMolecular dynamics |
| spellingShingle | Manoj Kumar Vashisth Junkai Hu Mingrui Liu Syed Hussain Basha Chen Yu Wenhua Huang In-Silico discovery of 17alpha-hydroxywithanolide-D as potential neuroprotective allosteric modulator of NMDA receptor targeting Alzheimer’s disease Scientific Reports Alzheimer’s disease N-methyl-D-aspartate receptor Withania somnifera Virtual screening Docking Molecular dynamics |
| title | In-Silico discovery of 17alpha-hydroxywithanolide-D as potential neuroprotective allosteric modulator of NMDA receptor targeting Alzheimer’s disease |
| title_full | In-Silico discovery of 17alpha-hydroxywithanolide-D as potential neuroprotective allosteric modulator of NMDA receptor targeting Alzheimer’s disease |
| title_fullStr | In-Silico discovery of 17alpha-hydroxywithanolide-D as potential neuroprotective allosteric modulator of NMDA receptor targeting Alzheimer’s disease |
| title_full_unstemmed | In-Silico discovery of 17alpha-hydroxywithanolide-D as potential neuroprotective allosteric modulator of NMDA receptor targeting Alzheimer’s disease |
| title_short | In-Silico discovery of 17alpha-hydroxywithanolide-D as potential neuroprotective allosteric modulator of NMDA receptor targeting Alzheimer’s disease |
| title_sort | in silico discovery of 17alpha hydroxywithanolide d as potential neuroprotective allosteric modulator of nmda receptor targeting alzheimer s disease |
| topic | Alzheimer’s disease N-methyl-D-aspartate receptor Withania somnifera Virtual screening Docking Molecular dynamics |
| url | https://doi.org/10.1038/s41598-024-78975-2 |
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