Computational Identification of YQG-Like Small-molecule Inhibitors Targeting TIM-3 for Cancer Immunotherapy

Abstract

Aims: To identify potential small-molecule inhibitors of T-cell immunoglobulin and mucin domain-3 (TIM-3) through computational approaches and evaluate their interactions, stability, and structural dynamics. Study Design: A computational drug discovery study utilizing virtual screening, molecular docking, and molecular dynamics simulations. Methodology: A pharmacophore/similarity search was conducted using the PUBCHEM database, followed by molecular docking simulations to identify compounds with favorable binding properties to TIM-3. Three top-performing compounds (CID_146311758-TIM3, CID_164628526_TIM-3, and CID_146301996-TIM3) were analyzed further using molecular dynamics simulations to assess their binding stability, structural compactness, and hydrogen bond interactions. The study was conducted at the Department of Chemistry and Chemical Engineering, University of New Haven, USA, between January and December 2024. Results: CID_164628526_TIM-3 displayed stable binding (-8.6 kcal/mol), minimal fluctuations, and a compact structure closely resembling the reference compound YQG (-8.3 kcal/mol). CID_146311758-TIM3 (-8.6 kcal/mol) and CID_146301996-TIM3 (-8.4 kcal/mol) showed higher flexibility and fluctuations. Hydrogen bond analysis indicated that CID_164628526_TIM-3 formed fewer bonds on average. These findings suggest that CID_164628526_TIM-3 is a promising candidate for further investigation. Conclusion: This study highlights the potential of computational approaches to identify small-molecule inhibitors for TIM-3. CID_164628526_TIM-3 demonstrated superior binding energy (-8.6 kcal/mol) and stable interactions, closely resembling the reference compound YQG in structural integrity and hence providing a foundation for developing novel therapeutic agents targeting TIM-3 to enhance immune responses against tumors.