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Updated: Jun 12, 2026
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Generation of a RIP1 Knockout U937 Cell Line Using the CRISPR-Cas9 System
Published on: April 11, 2025
Structure-Based Design of Isoxazolidine RIPK1 Inhibitors for Neuroinflammation
Shamima Rahman Shila1, Mansour H Almatarneh2, Humaera Noor Suha1
1Department of Biochemistry and Microbiology, North South University, Dhaka, Bangladesh.
Journal of Computational Chemistry
|June 11, 2026
Summary
Compound 7 shows promise as a novel Alzheimer's disease (AD) therapeutic. This study identified it as a potent inhibitor of receptor-interacting protein kinase 1 (RIPK1), crucial in neuroinflammation and neuronal death.
Area of Science:
- Computational chemistry and drug discovery
- Neuroscience and pharmacology
- Molecular modeling and simulation
Background:
- Alzheimer's disease (AD) is a progressive neurodegenerative disorder linked to cognitive decline and neuronal loss.
- Aberrant activation of receptor-interacting protein kinase 1 (RIPK1) drives neuroinflammation and programmed cell death, presenting a key therapeutic target.
- Targeting RIPK1 offers a potential strategy for mitigating AD pathogenesis.
Purpose of the Study:
- To computationally identify novel inhibitors of RIPK1 from a library of isoxazolidine derivatives.
- To evaluate the binding affinity, electronic properties, and pharmacokinetic profile of potential RIPK1 inhibitors.
- To assess the stability and dynamic behavior of the most promising compound-target complex using molecular dynamics simulations.
Main Methods:
- Molecular docking was employed to screen 16 isoxazolidine derivatives against RIPK1 (PDB ID: 7XMK).
- Density functional theory (DFT) calculations were performed to determine electronic properties like the HOMO-LUMO energy gap.
- Lipinski's rule of five, Veber's criteria, and ADMET predictions (HIA, BBB permeability, toxicity) were assessed.
- 100 ns molecular dynamics (MD) simulations and principal component analysis (PCA) were utilized to evaluate complex stability.
Main Results:
- Compound 7 demonstrated the highest binding affinity to RIPK1 (-9.0 kcal/mol), surpassing reference inhibitors.
- DFT calculations revealed a favorable HOMO-LUMO energy gap of 5.209 eV, indicating electronic stability.
- Compound 7 exhibited excellent predicted ADMET properties, including high human intestinal absorption (HIA=1.0) and blood-brain barrier permeability (BBB=0.991).
- MD simulations confirmed the stability of the RIPK1-compound 7 complex, with acceptable RMSD (5.2–14.0 Å) and Rg (2.8–3.8 nm) fluctuations.
- PCA analysis supported the conformational stability of the complex.
Conclusions:
- Compound 7 is a highly promising RIPK1 inhibitor with favorable binding affinity and electronic properties.
- Its predicted pharmacokinetic and ADMET profiles suggest therapeutic potential for Alzheimer's disease.
- Further experimental validation is warranted to confirm compound 7's efficacy as an AD therapeutic agent.
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