A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology.
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 ex...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-01-01
|
| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000648&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849695180673777664 |
|---|---|
| author | Jacob D Durrant Rommie E Amaro Lei Xie Michael D Urbaniak Michael A J Ferguson Antti Haapalainen Zhijun Chen Anne Marie Di Guilmi Frank Wunder Philip E Bourne J Andrew McCammon |
| author_facet | Jacob D Durrant Rommie E Amaro Lei Xie Michael D Urbaniak Michael A J Ferguson Antti Haapalainen Zhijun Chen Anne Marie Di Guilmi Frank Wunder Philip E Bourne J Andrew McCammon |
| author_sort | Jacob D Durrant |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-fd9f4c1442ef480280b47cb5132cd1c8 |
| institution | DOAJ |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2010-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-fd9f4c1442ef480280b47cb5132cd1c82025-08-20T03:19:50ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582010-01-0161e100064810.1371/journal.pcbi.1000648A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology.Jacob D DurrantRommie E AmaroLei XieMichael D UrbaniakMichael A J FergusonAntti HaapalainenZhijun ChenAnne Marie Di GuilmiFrank WunderPhilip E BourneJ Andrew McCammonConventional 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.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000648&type=printable |
| spellingShingle | Jacob D Durrant Rommie E Amaro Lei Xie Michael D Urbaniak Michael A J Ferguson Antti Haapalainen Zhijun Chen Anne Marie Di Guilmi Frank Wunder Philip E Bourne J Andrew McCammon A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology. PLoS Computational Biology |
| title | A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology. |
| title_full | A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology. |
| title_fullStr | A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology. |
| title_full_unstemmed | A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology. |
| title_short | A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology. |
| title_sort | multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000648&type=printable |
| work_keys_str_mv | AT jacobddurrant amultidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT rommieeamaro amultidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT leixie amultidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT michaeldurbaniak amultidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT michaelajferguson amultidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT anttihaapalainen amultidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT zhijunchen amultidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT annemariediguilmi amultidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT frankwunder amultidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT philipebourne amultidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT jandrewmccammon amultidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT jacobddurrant multidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT rommieeamaro multidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT leixie multidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT michaeldurbaniak multidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT michaelajferguson multidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT anttihaapalainen multidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT zhijunchen multidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT annemariediguilmi multidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT frankwunder multidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT philipebourne multidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology AT jandrewmccammon multidimensionalstrategytodetectpolypharmacologicaltargetsintheabsenceofstructuralandsequencehomology |