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 study 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 wetlab studies are needed to confirm the potency of the studied compounds.

Investigation of Methyl-5-(pentan-3-yloxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxyhydrazide Derivatives as Potential Inhibitors of COVID-19 Main Protease: DFT and Molecular Docking Study

“…Prior to DFT quantum calculations, we first conducted a conformer distribution examination on each of the compounds using B3LYP hybrid functional methods with the 6-31G* basis set implemented in Spartan 14 computational software. 37 We used the most stable conformer for subsequent calculations, which was carried out on an HP 2000 Notebook computer with an Intel® Core™ i3-3120M CPU @ 2.50 GHz, 296 GB SSD, and 4.00 GB RAM. Our calculations included determining the frontier molecular orbital energies, highest occupied molecular orbital energy (E HOMO ), and lowest unoccupied molecular orbital energy (E LUMO ).…”

“…Quantum parameters such as ionization energy (I), electron affinity (A), chemical hardness (η), electronic chemical potential (µ), and electronegativity (χ) were computed from the frontier molecular orbital energies using the following relationships as presented in Equations ( 1) to ( 7). [37][38][39][40] Energy gap…”

Introduction to The Special Issue: Novel Molecular Pathways and Therapeutic Challenges in Neurodegenerative Diseases

“…Additionally, Hui et al [13] highlight the significant role of interferon-␣ in modifying the metabolic pathways in neuronal cell death. Ishabiyi and co-workers [14] developed a novel computational evaluation methodology to assess Azadirachta indica-derived bioactive compounds as potential inhibitors of the NLRP3 pathway as a possible treatment for AD. This study may lead to novel ideas for potential drug discovery.…”