標題: Pros and Cons of the Tuberculosis Drugome Approach - An Empirical Analysis
作者: Chen, Feng-Chi
Liao, Yu-Chieh
Huang, Jie-Mao
Lin, Chieh-Hua
Chen, Yih-Yuan
Dou, Horng-Yunn
Hsiung, Chao Agnes
生物科技學系
Department of Biological Science and Technology
公開日期: 27-六月-2014
摘要: Drug-resistant Mycobacterium tuberculosis (MTB), the causative pathogen of tuberculosis (TB), has become a serious threat to global public health. Yet the development of novel drugs against MTB has been lagging. One potentially powerful approach to drug development is computation-aided repositioning of current drugs. However, the effectiveness of this approach has rarely been examined. Here we select the "TB drugome" approach - a protein structure-based method for drug repositioning for tuberculosis treatment - to (1) experimentally validate the efficacy of the identified drug candidates for inhibiting MTB growth, and (2) computationally examine how consistently drug candidates are prioritized, considering changes in input data. Twenty three drugs in the TB drugome were tested. Of them, only two drugs (tamoxifen and 4-hydroxytamoxifen) effectively suppressed MTB growth at relatively high concentrations. Both drugs significantly enhanced the inhibitory effects of three first-line anti-TB drugs (rifampin, isoniazid, and ethambutol). However, tamoxifen is not a top-listed drug in the TB drugome, and 4-hydroxytamoxifen is not approved for use in humans. Computational re-examination of the TB drugome indicated that the rankings were subject to technical and data-related biases. Thus, although our results support the effectiveness of the TB drugome approach for identifying drugs that can potentially be repositioned for stand-alone applications or for combination treatments for TB, the approach requires further refinements via incorporation of additional biological information. Our findings can also be extended to other structure-based drug repositioning methods.
URI: http://dx.doi.org/10.1371/journal.pone.0100829
http://hdl.handle.net/11536/24922
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0100829
期刊: PLOS ONE
Volume: 9
Issue: 6
起始頁: 
結束頁: 
顯示於類別:期刊論文


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