Drug discovery to inhibits processes lead by α5β1-fibronectin interaction

Tissue integrity and hence human health are both influenced by cell attachment to the extracellular matrix. Integrins are heterodimer cell surface receptors made up of two non-covalently coupled alpha and beta subunits that primarily govern cell motility, adhesion, differentiation, migration, and proliferation by interacting with cell-cell adhesion and cell-extracellular matrix. Integrin α5β1, also known as the ‘fibronectin receptor’, is a heterodimer composed of α5 and β1 subunits that has emerged as a key mediator in several human carcinomas. Several forms of human malignancies, including cell proliferation, angiogenesis, and tumor spread, are intimately associated with this kind of integrin. The purpose of this work is the search for small inhibitor molecules capable of downregulating the interactions between α5β1 and fibronectin. The aim has been to target specific sites used for the protein-protein binding between fibronectin and integrin. In order to efficiently find the proper compounds, a docking procedure has been performed in order to screen and rank different molecules. Then, applying molecular dynamic simulations and methods for evaluation of chemical drug-likeness, our research has resulted in a final ranking which we can use to build a ‘pharmacophore model’ ready to be used for constructing a database of novel molecules or for repurposing old ones. This drug discovery method will also give a better knowledge about the required interactions inhibitor molecules should engage to correctly bind into the α5β1 sites. The outcome of this drug development process will be to cause a decrease in the spread of cancer in different physiological environments.