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. 2017 Apr;7(1):141-150.
doi: 10.15171/apb.2017.018. Epub 2017 Apr 13.

Characterizing the Hot Spots Involved in RON-MSPβ Complex Formation Using In Silico Alanine Scanning Mutagenesis and Molecular Dynamics Simulation

Omid Zarei  1   2   3 , Maryam Hamzeh-Mivehroud  2   4 , Silvia Benvenuti  5 , Fulya Ustun-Alkan  6 , Siavoush Dastmalchi  2   4
Affiliations

Characterizing the Hot Spots Involved in RON-MSPβ Complex Formation Using In Silico Alanine Scanning Mutagenesis and Molecular Dynamics Simulation

Omid Zarei et al. Adv Pharm Bull. 2017 Apr.

Abstract

Purpose: 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 energy. Results: The 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.

Keywords: Alanine screening; Cancer; Drug design; MSP; Molecular dynamic simulation; RON.

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