Mechanistic Profiling of Ligand-Inhibitor Interactions for Integrin Receptor Modulation in Cancer Therapeutic Targeting
Vyom Sharma, Gaurav Sharma
Flower Mound High School, Flower Mound, USA
Eigen Sciences, Apex, USA
Publication date: November 20, 2025
Flower Mound High School, Flower Mound, USA
Eigen Sciences, Apex, USA
Publication date: November 20, 2025
DOI: http://doi.org/10.34614/JIYRC2025II20
ABSTRACT
Integrin receptors are proteins on the extracellular surface that facilitate the binding between cells and the extracellular matrix (ECM), holding pivotal roles in cell signaling. Some integrins aid in tumor progression and metastasis in cancerous tumors by allowing cancer cell migration in different organs and tissues. The integrin receptor contains alpha (α) and beta (β) subunits and interacts with specific ligands for inside-out cell signaling. By inhibiting the binding of these subunits, cell signaling in these tumor cells will be blocked. Recently, it has been discovered that a cavity inside the β propeller region of integrin αV is needed for the heterodimerization of integrin αVβ5, providing a space for therapeutic advancement. Therefore, we hypothesize that the β-propeller should have a druggable site, and a small molecule inhibitor can fit in the cavity and prevent the α and β subunits from interacting. This study uses computational methods, such as simulating molecular docking and graph neural network (GNN), to identify inhibitors interacting with αβ integrin receptors and disrupting the integrin heterodimerization. Five of the ligands tested computed well. Furthermore, these inhibitors could potentially prevent integrin activation. Considering the docking simulation, we have identified five ligands that bind to the β subunit of the integrin receptor. These ligands interact by forming predominantly hydrophobic bonds to the β-propeller protein. Our current work targets an exclusive class of integrin inhibitors that function by dissociating the α and β subunits of the integrin receptor.
Integrin receptors are proteins on the extracellular surface that facilitate the binding between cells and the extracellular matrix (ECM), holding pivotal roles in cell signaling. Some integrins aid in tumor progression and metastasis in cancerous tumors by allowing cancer cell migration in different organs and tissues. The integrin receptor contains alpha (α) and beta (β) subunits and interacts with specific ligands for inside-out cell signaling. By inhibiting the binding of these subunits, cell signaling in these tumor cells will be blocked. Recently, it has been discovered that a cavity inside the β propeller region of integrin αV is needed for the heterodimerization of integrin αVβ5, providing a space for therapeutic advancement. Therefore, we hypothesize that the β-propeller should have a druggable site, and a small molecule inhibitor can fit in the cavity and prevent the α and β subunits from interacting. This study uses computational methods, such as simulating molecular docking and graph neural network (GNN), to identify inhibitors interacting with αβ integrin receptors and disrupting the integrin heterodimerization. Five of the ligands tested computed well. Furthermore, these inhibitors could potentially prevent integrin activation. Considering the docking simulation, we have identified five ligands that bind to the β subunit of the integrin receptor. These ligands interact by forming predominantly hydrophobic bonds to the β-propeller protein. Our current work targets an exclusive class of integrin inhibitors that function by dissociating the α and β subunits of the integrin receptor.
