Structure-Based Design of Isoxazolidine RIPK1 Inhibitors for Neuroinflammation

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.