Computational Identification of YQG-Like Small-molecule Inhibitors Targeting TIM-3 for Cancer Immunotherapy
Winner Amaka Egejuru
Department of Public Health, University of New Haven, West Haven, CT, USA.
Abel Ujaigbe Egbemhenghe
Department of Chemistry and Biochemistry, Texas Technology University, Lubbock, Texas, USA.
Bamidele Samson Omotara
Department of Chemistry and Biochemistry, Texas Technology University, Lubbock, Texas, USA.
Christiana Oluwaseun Aderemi
Department of Public Health, University of New Haven, West Haven, CT, USA.
Ibidun Blessing Isaac
Department of Chemistry, University of Missouri, Saint Louis, 316 Benton Hall St. Louis MO, USA.
Emmanuel Parkay Oladokun
Department of Biotechnology, Illinois State University, Campus Box6130, Normal, Illinois, USA.
Pruthvirajsinh Rajendrasinh Solanki
Department of Chemistry and Chemical Engineering, University of New Haven, West Haven, CT, USA.
Ihunanya Meejay Kanu
Department of Epidemiology and Biotatistics, Jackson State University, Jackson, MS, USA.
Christopher Ddamulira
Department of Biomedical Engineering, University of New Haven, West Haven, CT, USA.
Ibrahim Tope Abdulrasaq
Department of Biomedical Engineering, University of Lagos, Idi-Araba, Lagos, Nigeria.
Yemisi Elizabeth Asibor
Department of Pure & Applied Chemistry, Osun State University, Osogbo, Osun State, Nigeria.
Onyinyechi Vera Ofoegbu
Department of Biochemistry, University of Lagos, Idi-Araba, Lagos, Nigeria.
Sheriff Olabisi Ogunyemi
Department of Biochemistry, University of Lagos, Idi-Araba, Lagos, Nigeria.
Cyril Obaro Agadagba
Department of Chemistry, Baylor University, Waco, TX 76706, USA.
Muhammad Qasim Ali
Department of Chemistry and Biochemistry, Texas Technology University, Lubbock, Texas, USA.
Olajide Enoch Aderemi *
Department of Chemistry, University of Missouri, Saint Louis, 316 Benton Hall St. Louis MO, USA.
*Author to whom correspondence should be addressed.
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.
Keywords: Computer-aided drug design, TIM-3, cancer immunotherapy, molecular docking, molecular dynamics simulation