A computational chemistry-based approach to optimizing PD-1/PD-L1 inhibitors

Area of Science:

• Medicinal Chemistry
• Immunology
• Computational Biology

Background:

• The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway is a critical immune checkpoint that regulates T-cell responses.
• Dysregulation of the PD-1/PD-L1 pathway is implicated in various cancers, making it a significant target for immunotherapy.
• Developing effective small molecule inhibitors for PD-1/PD-L1 is crucial for advancing cancer treatment.

Purpose of the Study:

• To design and synthesize novel small molecule inhibitors targeting the PD-1/PD-L1 immune checkpoint.
• To investigate the molecular interactions and inhibitory activity of these designed compounds.
• To provide a foundation for the development of new drugs targeting the PD-1/PD-L1 signaling pathway.

Main Methods:

• A library of 69 PD-1/PD-L1 inhibitors with a common backbone was curated from open databases.
• Molecular docking simulations were employed to investigate the binding mechanisms with the PD-L1 protein and explore active conformations.
• Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the biological activity and inhibition rates of newly designed inhibitors.

Main Results:

• Molecular docking revealed key interactions, including hydrogen bonds and π-π stacking, between inhibitors and PD-L1 residues like Tyr123, Gln66, and Phe67.
• The analysis identified specific amino acid residues (Tyr123, Gln66, Thr20, Met115, Asp122, Ile116) crucial for inhibitor binding.
• ELISA assays demonstrated high inhibition rates for four novel compounds, with compound N2 achieving a maximum inhibition rate of 68.53%.

Conclusions:

• The study successfully designed and synthesized novel small molecule inhibitors targeting the PD-1/PD-L1 pathway.
• Computational and experimental results highlight the potential of these compounds for modulating immune responses.
• These findings provide a valuable basis for further drug discovery efforts aimed at the PD-1/PD-L1 signaling pathway in cancer immunotherapy.