COMPUTATIONAL APPROACHES TOWARD UNDERSTANDING MOLECULAR MECHANISM OF LIGANDS TARGETING INTEGRIN RECEPTORS

Abstract

Integrins are a large family of heterodimeric transmembrane receptors that play a fundamental role in cellular adhesion, signal transduction, and communication with the extracellular matrix (ECM). They are composed of alpha (α) and beta (β) subunits that form a functional complex, which enables cells to sense mechanical and chemical changes in their microenvironment. Among their various functions, integrins mediate critical processes such as cell migration, survival, proliferation, and differentiation. Dysregulation of integrin-mediated signaling is implicated in a range of pathological conditions, including inflammation, fibrosis, and cancer, where they contribute to tumor progression, metastasis, and resistance to therapy by modulating the tumor microenvironment. One particularly important integrin is the α5β1 integrin, which specifically binds to fibronectin, an ECM protein involved in tissue repair and cellular signaling. The α5β1 integrin is crucial for regulating cell adhesion and migration through its interactions with fibronectin and its involvement in the dynamic remodeling of the ECM. This integrin plays a pivotal role in angiogenesis, the process of new blood vessel formation, which is a key feature of both wound healing and tumor growth. Aberrant α5β1 integrin signaling has been shown to promote cancer cell survival, invasion, and metastasis. Inflammatory environments further exacerbate α5β1 integrin dysregulation, making it a critical target in the study of cancer progression and chronic inflammation. In addition to its function in cancer, the α5β1 integrin has been implicated in chronic inflammatory diseases such as systemic inflammation, where its role in facilitating leukocyte migration and adhesion underscores its importance in immune responses. Ligands targeting α5β1 integrin can modulate its activity, either by activating or inhibiting its signaling pathways. Conventional ligands, such as peptides derived from fibronectin, have been widely studied for their ability to engage α5β1 integrin and initiate downstream signaling cascades involved in cell survival and migration. These conventional ligands often mimic natural ECM components, acting as agonists or antagonists of integrin-mediated signaling. More recently, non-conventional ligands, such as small molecules, antibodies, and engineered peptidomimetics, have emerged as novel tools for modulating α5β1 integrin function. These ligands offer the potential to selectively target α5β1 integrin in pathological conditions, disrupting aberrant integrin signaling without affecting normal tissue homeostasis. Understanding the molecular mechanisms through ii which both conventional and non-conventional ligands affect α5β1 integrin activity is critical for the development of therapeutics aimed at treating integrin-related diseases.