Insilico analysis of the pathogenic deletion mutations (CFTR-F508del) associated with cystic fibrosis disease

Cystic fibrosis(CF) is a life-threatening autosomal recessive disorder primaily caused by mutations in the CFTR gene that disrupt chloride ion transport across epithelial membranes. The deletion of phenylalanine at position 508 (F508del) which is the most pathogenic variant frequent, leading to misfolding of protein, defective channel gating, and accelerated degradtion of the CFTR protein. Although lvacaftor is an FDA-approved CFTR potentiator that improves channel opening probability, its exact interaction pattern with the F508del - mutated CFTR remains incompletely understood at the molecular level.

The present study aimed to elucidate the genetic and structural consequences of the F508del mutation and to characterize lvacaftor binding th the mutant CFTR using an integrative in silico workflow. By combining sequence analysis, physicochemical profiling, homolgy modeling, and molecular docking, the study sought to (i) identify conformational alterations caused by the F508del deletion, (ii) map key residues involved in lvacaftor binding, and (iii) provide a structural rationale that could guide the optimization of CFTR-targeted therapies and personalized treatment approaches for CF patients carrying the F508del mutation.

The CFTR gene and protein sequences were analyzed using NCBI, BLASTx, and ExPASy tools. Structural models of wild-type and F508del-mutant CFTR proteins were constructed via SWISS-Model, and physicochemical properties were computed. Molecular docking of Ivacaftor with the mutant CFTR was conducted using MOE (2024.06), and ligand-receptor interactions were analyzed.

The F508del mutation was confirmed to cause a three-nucleotide (CTT) deletion in exon 10, resulting in the loss of one amino acid in the translated protein. Structural modeling revealed disruption in the protein's 3D conformation. Physicochemical analysis showed minor changes in stability and hydropathy between wild-type and mutant forms. Docking simulations indicated that Ivacaftor binds favorably to the mutant CFTR (-7.45 kcal/mol), forming stabilizing π-H and H-π interactions, particularly with TRP 51, VAL 194, and ASP 195.

The integration of genetic, structural, and docking analyses supports the role of Ivacaftor as an effective modulator of F508del-CFTR function. The identified interaction hotspots offer a structural basis for optimizing CFTR-targeted therapeutics and support further exploration of personalized drug design in CF treatment.