Investigating novel chloride conductance activators for cystic fibrosis: Molecular docking and pharmacokinetics analysis of 3- (2-benzyloxy phenyl)isoxazoles and isoxazolines derivatives

Cystic fibrosis (CF) is a life-threatening genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to impaired chloride conductance and severe multisystem complications. This study investigates twenty-seven derivatives of 3- (2-benzyloxyphenyl)isoxazoles and isoxazolines as novel chloride conductance activators for CF therapy. Using molecular docking simulations, the binding affinities and interaction mechanisms of these ligands with the phosphorylated human CFTR protein (PDB: 8UBR) were evaluated. The top-performing ligands: UNX_23, UNX_13, UNX_5, UNX_15, UNX_16, UNX_22, and UNX_14 exhibited superior Moldock scores (ranging from -147.5 to -135.86 kcal/mol) compared to the reference drug Genistein (-91.45 kcal/mol), indicating stronger binding stability and potential therapeutic efficacy. Molecular dynamics (MD) simulations confirmed the stability of the top candidate, UNX_23, within the CFTR binding pocket over 100 ns. The UNX_23-CFTR complex demonstrated sTable backbone conformation (mean RMSD: 2.68 Å), low residue fluctuations in the binding site (mean RMSF: 1.25 Å), and persistent hydrogen bonding (average of 2.9 H-bonds), validating the docking predictions. Pharmacokinetic (ADMET: Absorption, Distribution, Metabolism, Excretion, Toxicity) profiling revealed favorable drug-like properties for all ligands, including high intestinal absorption (HIA > 93%), moderate-to-high blood-brain barrier permeability, and balanced distribution profiles. Notably, UNX_23 demonstrated optimal steric compatibility, balanced hydrogen and hydrophobic interactions, and compliance with Lipinski's rules, despite its synthetic complexity. Toxicity assessments indicated no mutagenic risks, though some ligands (e.g., UNX_5 and UNX_23) showed moderate hERG II inhibition, warranting further cardiac safety studies. The study highlights UNX_23 as a promising lead candidate due to its exceptional binding affinity, dynamic stability, pharmacokinetic suitability, and potential for oral bioavailability. These findings provide a foundation for developing novel CFTR modulators, offering insights into structure-activity relationships and therapeutic optimization for cystic fibrosis treatment.