Comparative Analysis of Rac1 Binding Efficiency With Different Classes of Ligands: Morpholines, Flavonoids and Imidazoles

Abstract

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.

Drug Discovery of Plausible Lead Natural Compounds That Target the Insulin Signaling Pathway: Bioinformatics Approaches

“…RAC1 has been intensively targeted in the last decades due to its confirmed extraordinary regulation roles. For example, a chemobioinformatics workflow is conducted to address drug design aspects with special reference to RAC1 [ 251 ]. The pipeline included the chemical abstract system (CAS) data mining, structural bioinformatics analysis, docking, and exploratory statistics.…”

“…To define protein domains that surround the residues, Doolittle hydrophobicity profiles have been analyzed [ 258 ]. This profile also assesses solvent accessibility, which could show favorable ligand binding sites [ 251 ]. Only a subset of flavonoids (24 out of 751), morpholines (10 out 528), and imidazoles (15 out of 709) was found to preferentially bind with RAC1 exactly in the region: Asp65-Arg-66-Arg68-Pro69 and Ala95-Lys96-Pro99-Glu100-His103-His104.…”

Molecular docking of ursolic acid and Staphylococcus aureus ATPase for antibacterial therapy

“…Molecular docking is nowadays extensively used in drug discovery for a great number of pathologies [40][41][42][43][44][45] Aim of our study was to preliminary evaluate if UA could modulate ATP amount by inhibiting ATP hydrolysis (in MRSA). Moreover, knowledge of the binding region could suggest insights about possible synergy with other drugs.…”

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