Comparative analysis of Rac1 binding efficiency with different classes of ligands: morpholines, flavonoids and imidazoles.

The focal adhesion pathway has a great impact on cellular growth and survival. Its disregulation is correlated with the loss of cellular mechanical properties. Such modifications are, in many cases, associated with pathologies such as cancer and cardiovascular diseases. Actin remodeling is a critical reaction cascade embedded in focal adhesion pathway, and Rac1 is one of the proteins involved in actin remodeling. In order to design highly selective pharmacophores against this target, it is necessary to maximize the binding affinity of chemical entities against Rac1. To this purpose we propose an integrative chemo-bioinformatics tool to screen ligand specificity for a target protein. Our integrative workflow includes chemo-informatics data mining (Chemical System), structural bioinformatics and combined exploratory data analysis. We have applied this integrative chemo-bioinformatics workflow to a comparative analysis of three different classes of ligands (morpholines, flavonoids and imidazoles) against the Rac1 protein. Our analysis emphasizes the presence of several ligands that preferentially dock Rac1 in the domain that seems to be responsible for Rac1-phospholipase C gamma 1 interaction. Recent studies have highlighted the Rac1 and PLC interactions in platelet adhesion. Our study has highlighted the role of Rac1-PLC gamma1 interaction in cytoskeleton remodeling associated with cardiovascular diseases. Rac1 PLC interaction is Calcium dependent. This suggest that some of the analysed ligands, could be used to control the Calcium dependent cytoskeleton remodeling since they dock Rac1 in the switch 2 domain. Our results, in a nanotechnology perspective, also endorse the use Rac1's switch 2 domain suitable for new highly specific biosensors.