New strategy for drug discovery by large-scale association analysis of molecular networks of different species.

Bo Zhang,Xuetong Chen,Yan Li,Chao Huang,Aiping Lu,Ziyin Wu,Yuerong Li,Fukai Gong,Xiaoyan Yang,Chunli Zheng,Shuo Gao,Yingxue Fu,Wenjuan Zhang,Yonghua Wang,Xiaoyu Chen

doi:10.1038/srep21872

Abstract

The development of modern omics technology has not significantly improved the efficiency of drug development. Rather precise and targeted drug discovery remains unsolved. Here a large-scale cross-species molecular network association (CSMNA) approach for targeted drug screening from natural sources is presented. The algorithm integrates molecular network omics data from humans and 267 plants and microbes, establishing the biological relationships between them and extracting evolutionarily convergent chemicals. This technique allows the researcher to assess targeted drugs for specific human diseases based on specific plant or microbe pathways. In a perspective validation, connections between the plant Halliwell-Asada (HA) cycle and the human Nrf2-ARE pathway were verified and the manner by which the HA cycle molecules act on the human Nrf2-ARE pathway as antioxidants was determined. This shows the potential applicability of this approach in drug discovery. The current method integrates disparate evolutionary species into chemico-biologically coherent circuits, suggesting a new cross-species omics analysis strategy for rational drug development.

Highlights

A comparative genome analysis revealed that 70% of human cancer genes have orthologues in Arabidopsis[17]; and plants and humans can generate structurally similar fatty acid oxidation products in response to wounding[15]
One can start from a disease and look for natural products that can be used as drugs to treat it, or can start from a compound and try to identify the disease that it can target by understanding its pharmacological activity
Because of limited availability of disease models, the technical difficulties of compound extraction, and other related technical problems, investigators are largely working in a blind fashion during the drug development process

Summary

Introduction

A comparative genome analysis revealed that 70% of human cancer genes have orthologues in Arabidopsis[17]; and plants and humans can generate structurally similar fatty acid oxidation products in response to wounding (e.g., jasmonic acid in plants and prostaglandins in humans)[15]. We present a cross-species molecular network association (CSMNA) profile to define chemical and biological connections between humans and 267 other species of plants, fungi and bacteria; and to identify pharmacologically active chemicals from massive NPs. CSMNA is based on the hypothesis that human and plants/ microbes have similar signaling chemicals and biochemical networks in specific functional categories so that molecules produced by different species may overlap functionally (Fig. 1). CSMNA is based on the hypothesis that human and plants/ microbes have similar signaling chemicals and biochemical networks in specific functional categories so that molecules produced by different species may overlap functionally (Fig. 1) This technique can be used for targeted screening of bioactive chemicals that regulate certain human pathways via identifying chemico-biologically associated pathways in a specific plant or microbe. We verified the chemical and biological relationships between the plant Halliwell-Asada (HA) cycle and the human Nrf2-ARE pathway, and how HA cycle related nature chemicals modulate human Nrf2-ARE pathway against oxidative damage

Methods

Results

Conclusion