Identification of potentially high drug-like VEGFR2/c-Met dual-target type II kinase inhibitors with symmetric skeletons based on structural screening

作者全名："Xie, Jiali; Zhang, Xiaoxuan; Meng, Dan; Li, Yihao; Deng, Ping"

作者地址："[Xie, Jiali; Zhang, Xiaoxuan; Meng, Dan; Li, Yihao; Deng, Ping] Chongqing Med Univ, Coll Pharm, Chongqing, Peoples R China; [Xie, Jiali; Zhang, Xiaoxuan; Meng, Dan; Deng, Ping] Chongqing Res Ctr Pharmaceut Engn, Chongqing, Peoples R China; [Xie, Jiali; Zhang, Xiaoxuan; Meng, Dan; Deng, Ping] Chongqing Key Res Lab Qual Evaluat & Safety Res AP, Chongqing, Peoples R China"

通信作者："Deng, P (通讯作者)，Chongqing Med Univ, Coll Pharm, Chongqing, Peoples R China."

来源：JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000969247700001

JCR分区：Q2

影响因子：2.7

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：VEGFR-2; c-Met dual inhibitor; kinase; pharmacophore model; molecular docking; molecular dynamics simulation

摘要："Vascular endothelial growth factor receptor 2 (VEGFR2) and c-Mesenchymal epithelial transition factor (c-Met) are tyrosine kinase receptors associated with the occurrence of malignant tumors. Studies have shown that inhibition of VEGFR2 promotes a feedback increase in c-Met, a mechanism linked to the emergence of resistance to VEGFR2 inhibitors. Therefore, treatment targeting both VEGFR2 and c-Met will have better application prospects. In this study, hierarchical virtual screening was performed on ZINC15, Molport and Mcule-ULTIMATE databases to identify potential VEGFR2/c-Met dual inhibitors. Firstly, the best pharmacophore model for each target was used to cross-screen the three databases, and the compounds that could match the two pharmacophore models were then retained based on the Fit Value of the respective crystal ligands. Compounds ZINC, MOL, and MLB named after their database sources were retained by binding pattern analysis and docking assessment. ADMET predictions indicated that ZINC had significantly higher oral bioavailability compared to the approved drug cabozantinib. This is likely due to ZINC's unique symmetrical backbone with less structure complexity, which may reduce the occurrence of adverse effects. Molecular dynamics simulations and binding free energy analysis showed that all three hit compounds were able to stably bind at the active site, but only ZINC could form high occupancy of hydrogen bonds with both VEGFR2 and c-Met, and also only ZINC had a higher binding free energy than crystal ligands, suggesting that ZINC was the most likely potential VEGFR2/c-Met dual-target inhibitor. This finding provides a promising starting point for the development of VEGFR2/c-Met dual-target inhibitors.Communicated by Ramaswamy H. Sarma"

基金机构："Program for Youth Innovation in Future Medicine, Chongqing Medical University [W0028]"

基金资助正文："This research was funded by Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0028)."