Phospholipid–Prednisolone Conjugates for Targeted IBD Therapy: Structural Design, Synthetic Approaches, Optimization, and Computational Evaluation

Vollständiger Abstract

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Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic disorder characterized by persistent intestinal inflammation. Although corticosteroids such as prednisolone effectively control disease symptoms, prolonged treatment is associated with severe side effects, including immune suppression and metabolic disturbances. To enable site-specific drug delivery, four phospholipid–linker–prednisolone conjugates were designed and synthesized as prodrugs targeting the overexpression of phospholipase A2 (PLA2) in inflamed intestinal tissues. The conjugates were prepared using a reversed synthetic strategy, in which the phospholipid–linker scaffold was assembled before drug coupling. The effect of spacer length on molecular conformation and predicted structural determinants of enzymatic activation was investigated through in silico analysis. Molecular docking simulations performed using the AutoDock Vina v1.2.7 framework, followed by structural and distance analysis in UCSF Chimera and 50 ns molecular dynamics simulations in GROMACS, suggested that linker length may influence ligand orientation, conformational orientation, ligand stability, and the spatial positioning of the ester bond relative to the catalytic histidine residue within the PLA2 active site. Among the two conjugates examined in detail by molecular dynamics, C6 maintained comparatively lower ligand mobility and a shorter average distance to the catalytic residue His47 than C12. These computational findings provide structural insights that may guide the future design and optimization of phospholipid-based corticosteroid prodrugs for targeted IBD therapy.