Identification of the therapeutic potential of novel TIGIT/PVR interaction blockers based advanced computational techniques and experimental validation

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.