Zarei Omid, Benvenuti Silvia, Ustun-Alkan Fulya, Hamzeh-Mivehroud Maryam, 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.
J Mol Model. 2017 Aug 19;23(9):267. doi: 10.1007/s00894-017-3437-2.
RON (Recepteur d'Origine Nantais) tyrosine kinase receptor is a promising target for therapeutic intervention in cancer therapy. The aim of this work was identification of RON-binding peptides using phage display and computational modeling their mode of binding. A 12-mer peptide phage library was utilized to perform biopanning against RON. The RON-binding ability of the selected peptide-displaying phage and their possible binding sites were examined by ELISA. Binding modes and affinities were also predicted by docking and molecular dynamics (MD) simulation. The results of ELISA experiment showed that P6 peptide displaying phage has higher affinity for RON compared to others and its binding site is located out of ligand binding site. Docking and MD simulation results also indicated higher affinity of P6 to RON as well as its exosite-binding feature. Taken together, our data suggest a capacity for P6 peptide (FEHSLYKEMTHL) to be utilized as RON binding agent, and hence be used for various purposes, including design of drug delivery systems for transferring cytotoxic agents to RON-positive cancer cells, interfering with RON signaling, peptidomimetics design, and diagnostic imaging.
RON（源自南特的受体）酪氨酸激酶受体是癌症治疗中一个有前景的治疗干预靶点。这项工作的目的是利用噬菌体展示技术鉴定RON结合肽，并通过计算模拟其结合模式。利用一个12肽噬菌体文库对RON进行生物淘选。通过酶联免疫吸附测定（ELISA）检测所选展示肽噬菌体的RON结合能力及其可能的结合位点。还通过对接和分子动力学（MD）模拟预测结合模式和亲和力。ELISA实验结果表明，与其他噬菌体相比，展示P6肽的噬菌体对RON具有更高的亲和力，其结合位点位于配体结合位点之外。对接和MD模拟结果也表明P6对RON具有更高的亲和力及其别构结合特征。综上所述，我们的数据表明P6肽（FEHSLYKEMTHL）有能力用作RON结合剂，因此可用于各种目的，包括设计将细胞毒性剂转运至RON阳性癌细胞的药物递送系统、干扰RON信号传导、肽模拟物设计和诊断成像。
