Targeting the NF-κB/IκBα complex via fragment-based E-Pharmacophore virtual screening and binary QSAR models

Area of Science:

• Computational chemistry and drug discovery
• Molecular modeling and simulation
• Pharmacology

Background:

• Nuclear Factor-kappa B (NF-κB) transcription factors are crucial regulators in immune, heart, glial, and neuronal cells.
• Dysregulation of NF-κB is implicated in cancer, chronic inflammation, and autoimmune diseases, making it a significant therapeutic target.

Purpose of the Study:

• To identify potent small molecule ligands targeting the NF-κB (p50/p65) heterodimer complex bound to IκBα.
• To utilize fragment-based e-pharmacophore screening and molecular docking to discover novel NF-κB inhibitors.

Main Methods:

• Employed fragment-based e-pharmacophore modeling using ZINC Clean Fragments and Glide fragments.
• Conducted high-throughput virtual screening (HTVS), and subsequent Glide SP/XP docking of large molecule libraries (Otava).
• Utilized molecular dynamics (MD) simulations and MM/GBSA analysis for structural and dynamical profiling of hit molecules.

Main Results:

• Identified 88 hit molecules from the Otava library, with 3 refined using MD simulations.
• The refined hit molecules exhibited low toxicity and potential therapeutic applications in heart failure, antiviral activity, asthma, and depression.
• Two specific ligands (Otava IDs: 1426436 and 6248112) demonstrated strong binding affinity to the NF-κB/IκBα complex.

Conclusions:

• The identified potent NF-κB/IκBα inhibitors offer a promising avenue for novel therapies against inflammation-mediated conditions and cancer.
• These findings facilitate further research and drug development efforts for NF-κB-related diseases.