Journal
PLOS COMPUTATIONAL BIOLOGY
Volume 6, Issue 1, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pcbi.1000648
Keywords
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Funding
- UCSD School of Medicine (NIH) [2T32GM007752-30, F32-GM077729, GM31749, GM078596]
- NSF MRAC [CHE060073N, MCB-0506593, MCA93S013]
- Howard Hughes Medical Institute
- National Biomedical Computation Resource (NIH) [P41 RR08605]
- Center for Theoretical Biological Physics (NSF) [PHY-0822283]
- Wellcome Trust [085622]
- AMDG [ANR-05-JCJC-0049-01]
- EUR-INTAFAR [LSHM-CT-2004-512138]
- Academy of Finland
- Sigrid Juselius Foundation
- NordForsk under the Nordic Centres of Excellence Programme on Food, Nutrition, and Health [070010]
- NATIONAL CENTER FOR RESEARCH RESOURCES [P41RR008605] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [F32GM077729, T32GM007752, R01GM031749, R01GM078596] Funding Source: NIH RePORTER
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Conventional drug design embraces the one gene, one drug, one disease philosophy. Polypharmacology, which focuses on multi-target drugs, has emerged as a new paradigm in drug discovery. The rational design of drugs that act via polypharmacological mechanisms can produce compounds that exhibit increased therapeutic potency and against which resistance is less likely to develop. Additionally, identifying multiple protein targets is also critical for side-effect prediction. One third of potential therapeutic compounds fail in clinical trials or are later removed from the market due to unacceptable side effects often caused by off-target binding. In the current work, we introduce a multidimensional strategy for the identification of secondary targets of known small-molecule inhibitors in the absence of global structural and sequence homology with the primary target protein. To demonstrate the utility of the strategy, we identify several targets of 4,5-dihydroxy-3-(1-naphthyldiazenyl)-2,7-naphthalenedisulfonic acid, a known micromolar inhibitor of Trypanosoma brucei RNA editing ligase 1. As it is capable of identifying potential secondary targets, the strategy described here may play a useful role in future efforts to reduce drug side effects and/or to increase polypharmacology.
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