E-pharmacophore based virtual screening of potent lead molecules against Cystic Fibrosis: An in silico study

Area of Science:

• Biochemistry
• Computational Chemistry
• Drug Discovery

Background:

• Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene, leading to a life-limiting illness with limited treatment options.
• The F508del mutation is the most common mutation, significantly impacting CFTR protein function.
• Developing novel therapeutic agents targeting the CFTR protein is crucial for improving patient outcomes.

Purpose of the Study:

• To identify novel lead compounds targeting the CFTR protein, specifically addressing the F508del mutation.
• To compare the efficacy of identified lead compounds with the existing drug Lumacaftor.
• To explore potential drug-like molecules for cystic fibrosis treatment.

Main Methods:

• Homology modeling of the CFTR NBD domain and refinement using apo dynamics.
• Pharmacophore mapping to define essential binding features for CFTR.
• Virtual screening of the NPASS database using a six-point pharmacophore model.
• In silico analysis including ADME/T, molecular dynamics, MM_GBSA, and DFT.

Main Results:

• A pharmacophore model with specific hydrogen-bonding and aromatic features was developed for CFTR.
• Virtual screening identified potential ligands from the NPASS database.
• Anguibactin (NPC41982) emerged as a top lead compound.
• Anguibactin demonstrated superior binding affinity and stability compared to Lumacaftor in silico.

Conclusions:

• Anguibactin is a promising lead compound for targeting the CFTR protein in cystic fibrosis.
• The identified compound exhibits enhanced binding characteristics over Lumacaftor.
• These findings provide a foundation for developing new drug-like molecules for cystic fibrosis therapy.