Zarei Omid, Hamzeh-Mivehroud Maryam, Benvenuti Silvia, Ustun-Alkan Fulya, Dastmalchi Siavoush
Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Adv Pharm Bull. 2017 Apr;7(1):141-150. doi: 10.15171/apb.2017.018. Epub 2017 Apr 13.
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). 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. The results revealed that Gln, Arg, Glu, Pro, Glu, and His residues from RON and Arg, His, Ser, Glu, and Arg from MSPβ may play important roles in protein-protein interaction between RON and MSP. 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.
蛋白质-蛋白质相互作用（PPI）在包括癌症在内的多种疾病发展过程中的作用，使其成为治疗干预和合理药物设计的有吸引力的靶点。RON（源自南特的受体）酪氨酸激酶受体作为癌症治疗中有前景的靶点已受到相当多的关注。RON通过其配体巨噬细胞刺激蛋白（MSP）激活是该受体最常见的激活机制。本研究的目的是进行计算机丙氨酸扫描诱变，并计算结合能以预测RON与MSPβ链（MSPβ）之间蛋白质-蛋白质界面中的热点。在这项工作中，RON-MSPβ复合物界面处的残基被突变为丙氨酸，然后使用分子动力学模拟来计算结合自由能。结果表明，RON中的Gln、Arg、Glu、Pro、Glu和His残基以及MSPβ中的Arg、His、Ser、Glu和Arg残基可能在RON与MSP之间的蛋白质-蛋白质相互作用中起重要作用。当目的是破坏RON-MSP相互作用时，识别这些RON热点在设计抗RON药物中很重要。同样，关于MSPβ关键氨基酸的获得信息可用于合理药物设计过程中，以开发MSP拮抗剂、开发需要抑制RON激活的新型MSP模拟肽以及设计实验性位点定向诱变研究。
