title: Anti-infectious drug repurposing using an integrated chemical genomics and structural systems biology approach.
abstract: The emergence of multi-drug and extensive drug resistance of microbes to antibiotics poses a great threat to human health. Although drug repurposing is a promising solution for accelerating the drug development process, its application to anti-infectious drug discovery is limited 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 Enrichment of Network Topological Similarity (ligENTS), to map the chemical universe to its global pharmacological space. ligENTS outperforms the state-of-the-art algorithms in identifying novel drug-target relationships. Furthermore, we integrate ligENTS with our structural systems biology platform to identify 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 against malaria. This study demonstrates the potential of an integrative chemical genomics and structural systems biology approach to drug repurposing.
authors.affiliation: Department of Computer Science, Hunter College, the City University of New York, 695 Park Avenue, New York City, NY 10065, U. S. A.. cng0003@hunter.cuny.edu.
authors.forename: Clara
authors.initials: C
authors.lastname: Ng
authors.forename: Ruth
authors.initials: R
authors.lastname: Hauptman
authors.forename: Yinliang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Philip E
authors.initials: PE
authors.lastname: Bourne
authors.forename: Lei
authors.initials: L
authors.lastname: Xie
mesh_terms: D000465:Algorithms; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D001185:Artificial Intelligence; D019295:Computational Biology; D058492:Drug Repositioning / Q000706:statistics & numerical data*; D018432:Drug Resistance, Multiple; D023281:Genomics; D006801:Humans; D008024:Ligands; D058990:Molecular Targeted Therapy; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics; D049490:Systems Biology
chemical_list: D000890:Anti-Infective Agents; D000962:Antimalarials; D008024:Ligands