Exploring FDA-approved small molecules for their potential as PD-1/PD-L1 inhibitors: integrating computational...

Area of Science:

• Oncology
• Immunology
• Computational Chemistry

Background:

• The PD-1/PD-L1 axis is a critical immune checkpoint in cancer, suppressing T-cell activity and promoting tumor immune evasion.
• Monoclonal antibodies targeting PD-1/PD-L1 show clinical success but have limitations including side effects, poor permeability, and high cost.
• Small-molecule inhibitors (SMIs) are needed, and drug repurposing offers a faster, cheaper, and safer development path.

Purpose of the Study:

• To identify existing drugs that can be repurposed as inhibitors of the PD-1/PD-L1 interaction.
• To explore drug repurposing as a viable strategy for developing novel cancer immunotherapies.

Main Methods:

• A multi-tiered virtual screening approach using docking algorithms (Flare, Cresset) was employed.
• Molecular dynamics simulations (500 ns) were performed to assess binding stability and conformational dynamics.
• ELISA-based assays were utilized for experimental validation of inhibitory potential.

Main Results:

• Six potential drug candidates were identified through virtual screening.
• Molecular dynamics simulations provided insights into binding stability and interactions.
• Experimental validation confirmed the inhibitory potential of shortlisted compounds against PD-1/PD-L1.

Conclusions:

• Drug repurposing is a promising strategy for developing effective and affordable PD-1/PD-L1 inhibitors.
• The identified compounds represent potential leads for novel cancer immunotherapy agents.
• This approach can accelerate the development of new treatments targeting immune checkpoints.