Computer Aided Drug Design Technology For Dual C-Met And VEGFR2 Target Inhibitors

Objective:C-Met and vascular endothelial growth factor receptor 2(VEGFR2)are tyrosine kinase receptors related to many tumors.They are now thought to be related to the occurrence and development of many kinds of tumors.Previous studies have shown that inhibition of VEGFR2 causes an increase in the feedback of c-Met,which is associated with the production of resistance to VEGFR2 inhibitors.At the same time,there is a cross between c-Met and VEGFR2 on the signal pathway.Therefore,the c-Met and VEGFR2 double target inhibitors will have a better application prospect than the single VEGFR2 inhibitors.There are mainly two kinds of c-Met and VEGFR2 target inhibitors.Quinolones,quinolones and pyridine types are relatively single,and their toxic and side effects are relatively large.Recently,more and more natural products have been found to have anti-tumor activity.However,no natural products have been found yet,and c-Met and VEGFR2 inhibitory activities have been reported.Therefore,it is of great significance to find the natural products with c-Met and VEGFR2 inhibitory activity at the same time in order to broaden the structure type of the double target inhibitor.The purpose of this study is to discover the natural products with c-Met and VEGFR2inhibitory activity to identify the novel structure type for the dual target inhibitors development.Materials and methods:First,by analyzing the existing c-Met and VEGFR2co-crystallization models,we selected co crystallized 3CTJ and 3VHE as models to construct pharmacophore respectively.Then the natural product compound library was screened by the established pharmacophore model.The XSCORE software is used to predict the free combination of the initial screening results.Choose the top 8 compounds to be used for further analysis.According to the results of the analysis,the suitable compounds were selected for biological activity verification.The biological activity positive results were treated by molecular docking,and the structure-activity relationship analysis was used to guide the subsequent structural transformation.Results:Through the analysis of c-Met and VEGFR2 co-crystallization 3CTJ and 3VHE,two corresponding pharmacophore models were constructed.After validation,these two models were used for virtual screening of TCM natural products library.The results were predicted by XSCORE free binding energy.The results showed that top eight of these compounds showed potential c-Met and VEGFR2 inhibitory activity in the simulation.The biological activity of the results showed that the chrysoeriol(CAS:491-71-4)has good c-Met(K_d=12μM)and VEGFR2(K_d=11μM)binding affinity.Thus,chrysoeriol was a good leading compound for structural modification in future.To understand structure-activity relationship(SAR),we analyzed the SAR of engeletin(CAS:572-31-6),flavanones B(CAS:79995-67-8)and chrysoeriol by using the Discover Studio software.Results showed that the substituent on C-7 of chrysoeriol was the key groups which should be retained in future structure modification.What’s more,compounds could in better inhibitory profile if the substituent on C-3 of chrysoeriol was replaced by smaller hydrogen bond donor.Conclusion:In this paper,we found a natural product named chrysoeriol,as a potential dual c-Met and VEGFR2 kinase inhibitors.The subsequent research on molecular docking is a brief description of the structure-activity relationship of the related compounds.Our study identified the natural products with c-Met and VEGFR2inhibitory activity for the first time,and provided a new structural model for c-Met and VEGFR2 double target inhibitors.