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Liothyronine could block the programmed death-ligand 1 (PDL1) activity: an e-Pharmacophore modeling and virtual
Navid Pourzardosht1,2, Zahra Sadat Hashemi3, Maysam Mard-Soltani4
1Cellular and Molecular Research Center, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
Purpose:
The interaction between PD-L1 on tumor cells and the programmed death 1 (PD1) on immune cells helps them to escape the immune system elimination. Therefore, developing therapeutic agents to block this interaction has garnered a lot of attention as a therapeutic approach. In the present study, we have tried to screen for an inhibitory compound to inhibit the interaction between the PD1/PD-L1 molecules.
Methods:
In this regard, the structure of PD-L1 and its inhibitor were prepared and employed to generate an e-Pharmacophore model. A library of approved compounds was prepared and toxicity analysis using Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) predictor was performed. The built e-Pharmacophore model was validated and used to screen the prepared compound library. Ligand docking and binding energy calculation were performed on the screened ligands.
Results:
A seven-feature e-Pharmacophore model was generated using the PD-L1 complex. All of the compounds within the library passed the ADMET criteria. Performing the virtual screening, only 79 compounds have survived the criteria to fit four pharmacophoric features. The compound with the highest binding energy was the liothyronine (T3).
Conclusion:
The ability of T3 in PD1/PD-L1 checkpoint blockade along with its potential in T4 reduction could be a desirable combination in cancer treatment. These abilities of T3 could be used to restore the ability of the immune system to eliminate tumor cells.
Insights
Researchers screened for compounds inhibiting the PD1/PD-L1 interaction, crucial for cancer immune evasion. Liothyronine (T3) showed the highest binding energy, suggesting potential for cancer therapy by blocking this immune checkpoint.
Area of Science:
- Computational chemistry
- Immunology
- Drug discovery
Background:
- The programmed death-ligand 1 (PD-L1) on tumor cells interacts with programmed death 1 (PD1) on immune cells, enabling immune evasion.
- Blocking the PD1/PD-L1 interaction is a promising cancer therapeutic strategy.
Purpose of the Study:
- To screen for novel inhibitory compounds targeting the PD1/PD-L1 interaction.
- To identify potential therapeutic agents for cancer treatment by modulating immune checkpoints.
Main Methods:
- Generation of an e-Pharmacophore model based on PD-L1 structure.
- Virtual screening of an approved drug library using the e-Pharmacophore model.
- Toxicity analysis (ADMET) and ligand docking with binding energy calculations.
Main Results:
- A seven-feature e-Pharmacophore model was successfully developed.
- 79 compounds from the library met the screening criteria after ADMET analysis.
- Liothyronine (T3) exhibited the highest binding energy among the screened compounds.
Conclusions:
- Liothyronine (T3) demonstrates potential for PD1/PD-L1 checkpoint blockade.
- T3's dual action, including potential T4 reduction, may enhance cancer treatment efficacy.
- T3 could help restore the immune system's ability to eliminate tumor cells.
