ANTI-INFECTIOUS DRUG REPURPOSING USING AN INTEGRATED CHEMICAL GENOMICS AND STRUCTURAL SYSTEMS BIOLOGY APPROACH

摘要

The emergence of multi-drug and extensive drug resistance of microbes to antibiotics poses a great threat to human health. Although drug re purposing is a prom ising sol ution for accele rating t he drug development process, its application to anti-infectious drug discovery is lim ited by the scope of existing phenotype-, ligand-, or target-based methods. In this paper we introduce a new computational strategy to determine the genome-wide molecular targets of bioactive compounds in both human and bacterial genomes. Our method is based on the use of a novel algorithm, ligand E nrichment of Net work T opological Sim ilarity (1 igENTS), t o m ap t he che mical uni verse t o i ts global pharmacological space .1 igENTS outperforms t he st ate-of-the-art al gorithms i n i dentifying n ovel drug-target relationships. Furthermore, we i ntegrate ligENTS with o ur st ructural sy stems bi ology platform t o i dentify drug repurposing opportunities via target similarity profiling. Using this integrated strategy, we have identified novel P. falciparum targets of drug-like active compounds from the Malaria Box, and suggest that a number of approved drugs may be active agai nst m alaria. T his study dem onstrates the po tential of an in tegrative ch emical g enomics an d structural systems biology approach to drug repurposing.