Background
Development of drugs that simultaneously target multiple proteins could improve efficacy, particularly in the treatment of complex diseases (e.g. cancer and central nervous system disorders). We have introduced Space-Related Pharmamotif (SRPmotif) method to identify pharma-interfaces sharing similar binding environments. However, the atomic interaction between a compound and a protein is important to understand that a compound target a protein. To combine similar binding environments and protein-compound interactions would provide the opportunities to explore the molecular binding mechanisms.
Results
In this study, we proposed a new concept of "homopharma" to describe a group of protein-compound interactions. A homopharma is a set of proteins with conserved sub-binding environment at the protein-compound interfaces and a set of compounds with similar topology. The results demonstrated that complexes of a homopharma group would perform similar protein-compound interactions and comprise conserved specific residues and important functional sites. Based on homopharma groups, four flavonoid derivatives were tested against 32 human protein kinases using in vitro enzymatic profiling. The experimental results identified 56 novel protein-compound interactions. 25 of 56 interactions may have IC50 values of less than 1 μM. Some novel protein-compound interactions suggest that these flavonoids could be used as anticancer compounds, such as oral and colon cancer.
Conclusions
The experimental results showed that new concept homopharma is not only useful to identify potential targets of compounds, but also can reveal the key binding environment. Moreover, it would useful for discovering the new usages for existing drugs. We believe that this approach can be further applied to understand molecular binding mechanisms and provide new concept about drug development.