Identification of the therapeutic potential of novel TIGIT/PVR interaction blockers based advanced computational
Xudong Lü1, Xiyu Wei1, Chenyu Wang2
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Abstract:
The inhibition of the TIGIT/PVR interaction demonstrates considerable anticancer properties by enhancing the cytotoxic activity of natural killer (NK) and CD8+ T cells. However, the development of small molecule inhibitors that target TIGIT is currently limited. In this study, small molecules with the capacity to bind TIGIT and block the TIGIT/PVR interaction were screened through an advanced computational process, subsequently confirmed by blocking assays. Combined machine learning model XGBOOST and centroid-based molecular docking were employed to expeditiously exclude negative molecules, thereby reducing the chemical space. Subsequently, a blockade assay targeting the TIGIT/PVR interaction was conducted on 14 candidate molecules along with positive control, wherein compound MCULE-5547257859 exhibited the most potent inhibitory effect. Molecular dynamics simulations and binding free energy analyses revealed that compound MCULE-5547257859 possesses a thermodynamically stable conformation, indicative of a stronger binding affinity to TIGIT. In conclusion, our investigation has delineated that compound MCULE-5547257859 effectively impedes the TIGIT/PVR interaction, thereby offering a novel therapeutic modality for oncology.
Insights
Researchers identified a novel small molecule, MCULE-5547257859, that effectively blocks the TIGIT/PVR interaction. This compound enhances immune cell activity, offering a promising new avenue for cancer therapy.
Area of Science:
- Immunology
- Computational Chemistry
- Pharmacology
Background:
- The TIGIT/PVR pathway plays a crucial role in immune regulation and cancer progression.
- Inhibiting TIGIT/PVR interaction enhances cytotoxic activity of natural killer (NK) and CD8+ T cells, showing anticancer potential.
- Development of small molecule inhibitors targeting TIGIT remains a challenge.
Purpose of the Study:
- To identify novel small molecules capable of inhibiting the TIGIT/PVR interaction.
- To evaluate the therapeutic potential of identified compounds in cancer treatment.
Main Methods:
- Utilized a computational screening process combining XGBOOST machine learning and molecular docking to identify potential TIGIT inhibitors.
- Validated candidate molecules through in vitro blocking assays.
- Performed molecular dynamics simulations and binding free energy analyses to assess binding affinity and stability.
Main Results:
- A computational approach efficiently reduced the chemical space for inhibitor screening.
- Compound MCULE-5547257859 demonstrated the most potent inhibition of the TIGIT/PVR interaction in blocking assays.
- Molecular dynamics simulations confirmed a thermodynamically stable conformation and strong binding affinity of MCULE-5547257859 to TIGIT.
Conclusions:
- Compound MCULE-5547257859 effectively inhibits the TIGIT/PVR interaction.
- This compound represents a promising novel therapeutic candidate for oncological applications.
- The study highlights the potential of computational methods in accelerating drug discovery for cancer immunotherapy.
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