Molecular docking and molecular dynamics of hypoxia-inducible factor (HIF-1alpha): towards potential inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Computational Chemistry

Background:

• Hypoxia-Inducible Factor 1-alpha (HIF-1α) is crucial for cancer cell adaptation to low-oxygen environments.
• Identifying novel HIF-1α inhibitors is essential for developing new anti-cancer therapies.
• Virtual screening and molecular dynamics simulations are powerful tools for drug discovery.

Purpose of the Study:

• To identify novel inhibitors of HIF-1α through virtual screening of existing anticancer drugs.
• To evaluate the binding affinity and molecular dynamics of potential inhibitors with HIF-1α.
• To assess the preliminary safety and pharmacokinetic properties of identified compounds.

Main Methods:

• Molecular dynamics (MD) simulation of HIF-1α to understand its stable dynamic features.
• Virtual screening of 217 anticancer drugs against an optimized HIF-1α structure.
• Molecular docking and 200 ns MD simulations for top-ranked compounds (Nilotinib, Pycnidione, 2-ME2).
• MM-GBSA analysis to calculate binding free energies.

Main Results:

• Nilotinib and Pycnidione exhibited high binding affinities (-9.04 and -9.34 kcal/mol) to HIF-1α, surpassing the control (2-ME2, -6.68 kcal/mol).
• MD simulations indicated stable interactions, with Nilotinib showing favorable dynamics (lower RMSD, higher SASA, lower RMSF, flatter Rg).
• MM-GBSA confirmed strong binding energies for Nilotinib (-23.77 ± 5.29 kcal/mol) and Pycnidione (-21.85 ± 4.24 kcal/mol).

Conclusions:

• Nilotinib and Pycnidione are identified as competitive inhibitors of HIF-1α with significant binding affinity.
• Nilotinib demonstrates consistent and favorable molecular-dynamic properties.
• These compounds possess favorable preliminary safety profiles (blood-brain barrier penetration, non-carcinogenic, low acute oral toxicity, low CYP inhibition), warranting further investigation into their therapeutic potential in hypoxia-driven cancers.