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Structure-Based Design of Isoxazolidine RIPK1 Inhibitors for Neuroinflammation
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DOI：10.1002/jcc.70411.png)
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Abstract
En 中文
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment and neuronal loss. Aberrant activation of receptor-interacting protein kinase 1 (RIPK1) plays a critical role in neuroinflammation and programmed neuronal death, making it an attractive therapeutic target. In this computational study, 16 isoxazolidine derivatives (1–16) were evaluated alongside seven reference inhibitors to identify potential RIPK1 blockers. Molecular docking analyses revealed that compound 7 exhibited the highest binding affinity toward RIPK1 (PDB ID: 7XMK), with a binding energy of −9.0 kcal mol−1, outperforming established inhibitors and demonstrating broad activity against AD-related targets. Density functional theory calculations showed a HOMO–LUMO energy gap of 5.209 eV, indicating favorable electronic stability. Compound 7 complied with Lipinski's rule of five and Veber's criteria and displayed excellent predictive ADMET properties, including high human intestinal absorption (HIA = 1.0), strong blood–brain barrier permeability (BBB = 0.991), and low predicted toxicity. Molecular dynamics (MD) simulations conducted over 100 ns at temperatures ranging from 300 to 320 K confirmed the stability of the RIPK1–compound 7 complex. The root-mean-square deviation (RMSD) values ranged from 5.2 to 14.0 Å (0.52–1.40 nm), indicating acceptable structural fluctuations throughout the simulation. Additionally, the radius of gyration (Rg) ranged from 2.8 to 3.8 nm, indicating that the complex maintained a relatively stable, compact conformation throughout the simulation. Principal component analysis further supported these findings, yielding cosine similarity values of 0.86–0.95. Collectively, these results highlight compound 7 as a promising RIPK1 inhibitor with favorable pharmacokinetic, electronic, and dynamic properties, underscoring its potential as a therapeutic candidate for AD.
Keywords:
ADMET
DFT
isoxazolidine derivatives
molecular docking
molecular dynamics
PCA
RIPK1
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