吉林大学学报（理学版）2024，Vol.62Issue(1)：181-188,8.DOI:10.13413/j.cnki.jdxblxb.2023170
新型靶向αvβ6多肽的设计、合成与亲和力评价
Design,Synthesis and Affinity Evaluation of Novel Targeted αvβ6 Polypeptides
摘要
Abstract
We designed and screened αvβ6 polypeptide ligands with new structure by using computer-aided drug design strategy and solid-phase synthesis method,and determined the binding affinity between the polypeptide ligands and αvβ6 by using enzyme-linked immunosorbent assay(ELISA)to establish a screening scheme for αvβ6 polypeptide ligands.Firstly,Sybyl-X 1.3 was used to perform molecular docking of the αvβ6 polypeptide ligands and natural ligands.Secondly,Amber 16 was used to perform molecular dynamics simulation to determine the binding mode between the polypeptide ligands and αvβ6 protein,and RGDLXXL(X was any amino acid)was used as the core structure of the polypeptide ligand,the virtual peptide library was constructed by gradual extension of amino acids,polypeptide ligands with a length of 7-10 amino acids were screened,and new polypeptide ligands different from the core of RGDLXXL were designed and screened by similar amino acid substitution method.Finally,the newly designed polypeptide ligands were synthesized by solid-phase synthesis method,and the binding affinity of polypeptide ligand-αvβ6 was determined by indirect ELISA method.The molecular docking and molecular dynamics simulation results of polypeptide ligands and natural ligands show that the binding of αvβ6 to the ligand is mainly achieved through the hydrogen bond formation between Asp218 and the polypeptide ligand,and the metal chelation between Mg2+and the polypeptide ligand.Combined with virtual combination screening and similar amino acid substitution,we find that polypeptides such as GRTDLGTLLFR,GRRTDLATIHG,RTDVGRVRGRG and RGDVGRVGR all meet this binding pattern,and the affinity between RTDVGRVRGRG and αvβ6 is 10.76 μmol/L.Therefore,RTDVGRVRGRG and αvβ6 have a good affinity and are a new αvβ6 polypeptide ligand.关键词
整合素αvβ6/多肽配体/药物设计/亲和力/酶联免疫吸附法Key words
integrin αvβ6/polypeptide/drug design/affinity/enzyme-linked immunosorbent assay(ELISA)分类
医药卫生引用本文复制引用
李跃鹏,王远强..新型靶向αvβ6多肽的设计、合成与亲和力评价[J].吉林大学学报（理学版）,2024,62(1):181-188,8.基金项目
重庆市科学技术局自然科学基金(批准号:CSTB2022NSCQ-MSX1327)和重庆市人力资源和社会保障局留学人员回国创业创新支持计划项目(批准号:cx2020012). （批准号:CSTB2022NSCQ-MSX1327）
