Homopharma: a new concept for exploring the molecular binding mechanisms and drug repurposing

Drugs that simultaneously target multiple proteins often improve efficacy, particularly in the treatment of complex diseases such as cancers and central nervous system disorders. Many approaches have been proposed to identify the potential targets of a drug. Recently, we have introduced Space-Related Pharmamotif (SRPmotif) method to recognize the proteins that share similar binding environments. In addition, compounds with similar topology may bind to similar proteins and have similar protein-compound interactions. However, few studies have focused on exploring the relationships between binding environments and protein-compound interactions, which is important for understanding molecular binding mechanisms and helpful to be used in discovering drug repurposing.

In this study, we propose a new concept of "Homopharma", combining similar binding environments and protein-compound interaction profiles, to explore the molecular binding mechanisms and drug repurposing. A Homopharma consists of a set of proteins which have the conserved binding environment and a set of compounds that share similar structures and functional groups. These proteins and compounds present conserved interactions and similar physicochemical properties. Therefore, these compounds are often able to inhibit the proteins in a Homopharma. Our experimental results show that the proteins and compounds in a Homopharma often have similar protein-compound interactions, comprising conserved specific residues and functional sites. Based on the Homopharma concept, we selected four flavonoid derivatives and 32 human protein kinases for enzymatic profiling. Among these 128 bioassays, the IC50 of 56 and 25 flavonoid-kinase inhibitions are less than 10 μM and 1 μM, respectively. Furthermore, these experimental results suggest that these flavonoids can be used as anticancer compounds, such as oral and colorectal cancer drugs.

The experimental results show that the Homopharma is useful for identifying key binding environments of proteins and compounds and discovering new inhibitory effects. We believe that the Homopharma concept can have the potential for understanding molecular binding mechanisms and providing new clues for drug development.