Dataset Information

Computational Evaluation of Azadirachta indica-Derived Bioactive Compounds as Potential Inhibitors of NLRP3 in the Treatment of Alzheimer's Disease.

ABSTRACT:

Background

The development of therapeutic agents against Alzheimer's disease (AD) has stalled recently. Drug candidates targeting amyloid-β (Aβ) deposition have often failed clinical trials at different stages, prompting the search for novel targets for AD therapy. The NLRP3 inflammasome is an integral part of innate immunity, contributing to neuroinflammation and AD pathophysiology. Thus, it has become a promising new target for AD therapy.

Objective

The study sought to investigate the potential of bioactive compounds derived from Azadirachta-indica to inhibit the NLRP3 protein implicated in the pathophysiology of AD.

Methods

Structural bioinformatics via molecular docking and density functional theory (DFT) analysis was utilized for the identification of novel NLRP3 inhibitors from A. indica bioactive compounds. The compounds were further subjected to pharmacokinetic and drug-likeness analysis. Results obtained from the compounds were compared against that of oridonin, a known NLRP3 inhibitor.

Results

The studied compounds optimally saturated the binding site of the NLRP3 NACHT domain, forming principal interactions with the different amino acids at its binding site. The studied compounds also demonstrated better bioactivity and chemical reactivity as ascertained by DFT analysis and all the compounds except 7-desacetyl-7-benzoylazadiradione, which had two violations, conformed to Lipinski's rule of five.

Conclusion

In silico studies show that A. indica derived compounds have better inhibitory potential against NLRP3 and better pharmacokinetic profiles when compared with the reference ligand (oridonin). These compounds are thus proposed as novel NLRP3 inhibitors for the treatment of AD. Further wet-lab studies are needed to confirm the potency of the studied compounds.

SUBMITTER: Ishabiyi FO

PROVIDER: S-EPMC10473084 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Computational Evaluation of Azadirachta indica-Derived Bioactive Compounds as Potential Inhibitors of NLRP3 in the Treatment of Alzheimer's Disease.

Ishabiyi Felix Oluwasegun FO Ogidi James Okwudirichukwu JO Olukade Baliqis Adejoke BA Amorha Chizoba Christabel CC El-Sharkawy Lina Y LY Okolo Chukwuemeka Calistus CC Adeniyi Titilope Mary TM Atasie Nkechi Hope NH Ibrahim Abdulwasiu A Balogun Toheeb Adewale TA

Journal of Alzheimer's disease : JAD 20230101 s1

<h4>Background</h4>The development of therapeutic agents against Alzheimer's disease (AD) has stalled recently. Drug candidates targeting amyloid-β (Aβ) deposition have often failed clinical trials at different stages, prompting the search for novel targets for AD therapy. The NLRP3 inflammasome is an integral part of innate immunity, contributing to neuroinflammation and AD pathophysiology. Thus, it has become a promising new target for AD therapy.<h4>Objective</h4>The study sought to investiga ...[more]

PMID: 36683510

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Project description:BackgroundDengue fever is a viral disease caused by the dengue flavivirus and transmitted through mosquito bites in humans. According to the World Health Organization, severe dengue causes approximately 40,000 deaths annually, and nearly 4 billion people are at risk of dengue infection. The urgent need for effective treatments against the dengue virus has led to extensive research on potential bioactive compounds.ObjectiveIn this study, we utilized a network pharmacology approach to identify the DENV-2 capsid protein as an appropriate target for intervention. Subsequently, we selected a library of 537 phytochemicals derived from Azadirachta indica (Family: Meliaceae), known for their anti-dengue properties, to explore potential inhibitors of this protein.MethodsThe compound library was subjected to molecular docking to the capsid protein to identify potent inhibitors with high binding affinity. We selected 81 hits based on a thorough analysis of their binding affinities, particularly those exhibiting higher binding energy than the established inhibitor ST-148. After evaluating their binding characteristics, we identified two top-scored compounds and subjected them to molecular dynamics simulations to assess their stability and binding properties. Additionally, we predicted ADMET properties using in silico methods.ResultsOne of the inhibitors, [(5S,7R,8R,9R,10R,13R,17R)-17-[(2R)-2-hydroxy-5-oxo-2H-furan-4-yl]-4,4,8,10,13-pentamethyl-3-oxo-5,6,7,9,11,12,16,17-octahydrocyclopenta[a]phenanthren-7-yl] acetate (AI-59), showed the highest binding affinity at -10.4 kcal/mol. Another compound, epoxy-nimonol (AI-181), demonstrated the highest number of H-bonds with a binding affinity score of -9.5 kcal/mol. During molecular dynamics simulation studies, both compounds have exhibited noteworthy outcomes. Through molecular mechanics employing Generalized Born surface area (MM/GBSA) calculations, AI-59 and AI-181 displayed negative ΔG_bind scores of -74.99 and -83.91 kcal/mol, respectively.ConclusionThe hit compounds identified in the present investigation hold the potential for developing drugs targeting dengue virus infections. Furthermore, the knowledge gathered from this study serves as a foundation for the structure- or ligand-based exploration of anti-dengue compounds.

Dataset Information

Computational Evaluation of Azadirachta indica-Derived Bioactive Compounds as Potential Inhibitors of NLRP3 in the Treatment of Alzheimer's Disease.

Background

Objective

Methods

Results

Conclusion

Publications

Computational Evaluation of Azadirachta indica-Derived Bioactive Compounds as Potential Inhibitors of NLRP3 in the Treatment of Alzheimer's Disease.

Similar Datasets

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