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

Abstract

BackgroundDrugs 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.ResultsIn 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.ConclusionsThe 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.

An Integrated Genomic Strategy to Identify CHRNB4 as a Diagnostic/Prognostic Biomarker for Targeted Therapy in Head and Neck Cancer

“…On the basis of the results above, we considered the idea that CHRNB4 could be a potential therapeutic target for the inhibition of migration and invasion in smoking HNSCC patients. By using in-house methods and tools (Homopharma and iGEMDOCK) [60,73,74], we discovered an FDA-approved drug, called varenicline, as a potential CHRNB4 inhibitor (purchased from Sigma-Aldrich, #PZ0004). We utilized parental cell lines (FaDu and SCC25) and NNK-treated cell lines to examine the efficacy of the inhibition of migration and invasion by treating cells with varenicline at concentrations of 0, 0.1, 1, and 5 µM (Figure 8 and Data S5).…”

“…Primarily, we systematically integrated the genomic and clinical data of HNSCC patients ( Figure 1) and found neuronal acetylcholine receptor subunit beta-4 (CHRNB4), a kind of nAChR, whose gene expression was upregulated and associated with adverse prognosis in smoking patients. Furthermore, on the basis of our previous work and drug repurposing approach, "Homopharma" [60], we discovered that an FDA-approved smoking cessation agent, varenicline, inhibits CHRNB4 in long-term NNK-treated HNSCC cells. Our results indicate that CHRNB4 is able to determine whether patients who smoke have a favourable or adverse prognosis and that the invasion and migration of NNK-treated cells were decreased when CHRNB4 was inhibited.…”

InCoB2014: mining biological data from genomics for transforming industry and health

“…In the era of genomic medicine, it is possible that some approved drug molecules can be used for diseases other than those they were originally approved for. Yang and co-workers [ 23 ] propose the concept of "Homopharma", to combine similar drug binding environments to better understand molecular binding mechanisms for deploying approved drugs for other diseases, known as "repurposing." Tyagi et al [ 24 ] have optimized arylthioindole compounds for efficiently disrupting tubulin assembly towards anti-cancer therapy, using QSAR and molecular dynamics approaches.…”

Target Identification Using Homopharma and Network-Based Methods for Predicting Compounds Against Dengue Virus-Infected Cells

“…Using the homopharma concept, the topology and chemical functional group of an active compound that is similar to an active molecule would bind to the same target protein at the specific binding site. Previous studies have revealed the advantage and success of this technique in the search for new inhibiting mechanisms of known drugs for drug repurposing [36]. Moreover, there is also the ability to use the approach to predict the target of an active compound, which is one of the most critical steps to bridge the gap between experimental and computational studies [37].…”