广东药科大学学报2019，Vol.35Issue(1)：59-68,10.DOI:10.16809/j.cnki.2096-3653.2018102501
吲哚类Src/IGF-1R激酶双靶点抑制剂的分子对接和分子动力学研究
Study on the docking and molecular dynamics simulations of indole derivates as dual src/igf-1r inhibitors
摘要
Abstract
Objective To study the action mechanism of indoles furnished dual c-Src/IGF-1 R inhibitors with two receptors. Methods The binding modes of these compounds interacting with both c-Src and IGF-1 R kinases and the key amino acid residues at the binding pockets were revealed by molecular docking and molecular dynamics (MD) simulation. The binding free energy of these compounds to Src and IGF-1 R kinases was calculated by MM-PBSA method. Results The binding patterns of the inhibitors in two kinases were found to be very similar by docking, and the docking scores of these compounds were closely related to their experimental activities. The correlation coefficients of Src and IGF-1 R were R=0.800 and R=0.891, respectively. The RMSD and Z score of the two kinases protein superposition were 0.18 nm and 7.02 nm, respectively, and the protein sequence was 36.00％ identical, indicating that the Src and IGF-1 R protein chains were highly similar. Molecular dynamics further demonstrated the stability and rationality of docking results. The binding free energies of compounds had a good correlation with the experimental activities. MM-GBSA energy decomposition indicated that the hydrophobic interaction was the major driving force for the binding of compounds to Src and IGF-1 R. The hydrogen bond interactions between the ligands and residues Ser345 and Asp404 helped to stabilize the conformation of ligands at the Src binding pocket. Conclusion The results can provide information for better understanding of the action mechanism of these indole inhibitos and thus be helpful in design novel potent dual Src/IGF-1 R inhibitors.关键词
Src/IGF-1R/吲哚类化合物/分子对接/分子动力学模拟Key words
Src/IGF-1R/indole derivatives/docking/molecular dynamics simulation分类
医药卫生引用本文复制引用
郑晓杰,马少杰,吴文娟,郑康成..吲哚类Src/IGF-1R激酶双靶点抑制剂的分子对接和分子动力学研究[J].广东药科大学学报,2019,35(1):59-68,10.基金项目
广州市科技计划项目(2013J4100071) （2013J4100071）
