Implication of protein-protein interactions (PPIs) in development of many
diseases such as cancer makes them attractive for therapeutic intervention and
rational drug design. RON (Recepteur d’Origine Nantais) tyrosine kinase
receptor has gained considerable attention as promising target in cancer
therapy. The activation of RON via its ligand, macrophage stimulation protein
(MSP) is the most common mechanism of activation for this receptor. The aim of
the current study was to perform in silico alanine scanning mutagenesis
and to calculate binding energy for prediction of hot spots in protein-protein
interface between RON and MSPβ chain (MSPβ).
Methods: In this
work the residues at the interface of RON-MSPβ complex were mutated to alanine
and then molecular dynamics simulation was used to calculate binding free
results revealed that Gln193, Arg220, Glu287,
Pro288, Glu289, and His424 residues from RON
and Arg521, His528, Ser565, Glu658,
and Arg683 from MSPβ may play important roles in protein-protein
interaction between RON and MSP.
Conclusion: Identification of these RON hot spots is
important in designing anti-RON drugs when the aim is to disrupt RON-MSP
interaction. In the same way, the acquired information regarding the critical
amino acids of MSPβ can be used in the process of rational drug design for
developing MSP antagonizing agents, the development of novel MSP mimicking
peptides where inhibition of RON activation is required, and the design of
experimental site directed mutagenesis studies.