drug discovery using chemical systems biology repositioning the safe medicine comtan to treat multi-drug and extensively drug resistant tuberculosis使用化学药物发现系统生物学重新定位安全医学comtan治疗多种药物和广泛耐药结核病.pdfVIP

Drug Discovery Using Chemical Systems Biology: Repositioning the Safe Medicine Comtan to Treat Multi- Drug and Extensively Drug Resistant Tuberculosis 1¤. 2. 3. 2 4 4,5 Sarah L. Kinnings , Nina Liu , Nancy Buchmeier , Peter J. Tonge , Lei Xie *, Philip E. Bourne * 1 Department of Biology, University of York, York, United Kingdom, 2 Institute of Chemical Biology Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, New York, United States of America, 3 Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America, 4 San Diego Supercomputer Center, University of California San Diego, La Jolla, California, United States of America, 5 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America Abstract The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis around the world, including in industrialized nations, poses a great threat to human health and defines a need to develop new, effective and inexpensive anti-tubercular agents. Previously we developed a chemical systems biology approach to identify off-targets of major pharmaceuticals on a proteome-wide scale. In this paper we further demonstrate the value of this approach through the discovery that existing commercially available drugs, prescribed for the treatment of Parkinson’s disease, have the potential to treat MDR and XDR tuberculosis. These drugs, entacapone and tolcapone, are predicted to bind to the enzyme InhA and directly inhibit substrate binding. The prediction is validated by in vitro and InhA k