Computational modeling of fibronectin, integrin and their complexes: search for inhibitors of its interactions with integrins

The interactions between extracellular matrix fibronectin and various integrins through specific receptors are of fundamental importance in cellular response, cell-cell interactions, immunological and inflammatory events and thrombus formation. The integrin binding domains of FN have been widely investigates and they are represented by the Arg-Gly-Asp (RGD) domain and the nearby areas that help to extend the contact surface, represented by the Pro-His-Ser-Arg-Asn (PHSRN) domain, found in the 9th and 10th type III FN modules. The ability to modulate the various aspects of cellular adhesion, motility and proliferation identified the FN-IN interactions as potential target for therapeutic treatments, especially in cancer and associated conditions (like thrombosis, angiogenesis, osteoporosis). Some integrins types are particularly critical intermediaries in a wide spectrum of cancer abilities, especially angiogenesis. In the recent years, computational modelling, analysis and simulation offer the possibility to study and evaluate molecules in a completely simulated computational environment, avoiding expensive experiments and reducing the simulation time, particularly in drug development, where the amount of compounds to test can range in millions. By offering the possibilities to make diverse test on ligand affinity and compound docking, it can be easy to isolate the most promising compounds that could make, for example, excellent inhibitors of the FN-IN interactions, focusing on the interactions between the cancer phenotypes. In this work crystallographic fragments of FN and a computational model of the whole protein, obtained during a previous group project with professor Tuszinsky using M.O.E. (Molecular Operating Environment, https://www.chemcomp.com/index.htm) will be used to analyze the sites of interaction between FN and IN, focusing on the integrins involved in cancer processes and maintenance, and to perform docking and molecular dynamics simulations with different molecules to evaluate possible inhibitors of such interactions, to use as potential therapeutic drug candidates. The analysis on such mechanism could also elucidate the processes of these interactions and the conformational changes that follow, that will be compared to in vitro simulations and results. The complete homology model of FN was obtained during a project work in the Rational Drug Design course at Politecnico of Torino, leed by professor J. Tuszynski and M. Miceli. I’m grateful to all of my collegues that participated in the project work and helped obtaining the model used for this work.