| Renal cell carcinoma is one of the most common cancers,most of which are clear cell renal cell carcinoma,and there is a tendency to develop into other cancers.At present,targeting the hypoxia-inducible factor HIF-2α to treat cc RCC is a direct and effective method.Studies have shown that HIF-2α and the proto-oncogene c-Myc cooperate to promote cc RCC tumor progression,and HIF-2α promotes the expression of c-Myc in a c-Myc-dependent manner.At the same time,the overexpression of c-Myc is related to the progression and drug resistance of most human cancers.Although HIF-2α and cMyc are important drug targets,but they are both transcription factors and have always been considered "undruggable" targets,which brings great difficulties to structure-based drug design.With the development of structural biology,the stable crystal structures of the two target proteins have been resolved.On this basis,we have used virtual screening tools(mainly including molecular docking and MM-GBSA technology)to obtain a part that can be targeted for binding.And then,molecular dynamics simulations were used to study their binding to these protein systems.We first obtained a batch of compounds that can bind to HIF-2α protein through a standard and effective virtual screening program.After molecular dynamics simulation analysis,the two best-performing compounds,c1 and c2,were finally selected.The results showed that these two compounds can disturb the entire protein structure by affecting different parts.The presence of the c2 compound can decompose the dimer structure.The possibility of separation.We found a molecular skeleton with a higher frequency in the screening results,which believed that this skeleton has the potential to continue SAR optimization.In the next work,our purpose is to find a batch of compounds that can bind both HIF-2α and c-Myc protein.In the structure-based screening process,we selected a batch of TOP compounds and predicted their effects.The binding affinity of these compounds.Representative compounds C93106,C43257 and C41580 all showed good comprehensive binding scores.Our results indicate that the target compound can form a key interaction with the active site of the protein,and the 30 ns molecular dynamics simulation of the ligand-protein complex shows a stable binding conformation.This research has laid a theoretical foundation for the development of more effective and specific HIF-2α and c-Myc dual target inhibitors.In the end,we selected the two compounds c1 and c2 with the most potential and the same molecular skeleton for synthesis.Through halogenation reaction and amide condensation reaction,the target product is finally obtained,which lays the material foundation for biological activity determination and subsequent SAR analysis. |
