Bioactivity-Based Molecular Networking for the Discovery of Drug Leads in Natural Product Bioassay-Guided Fractionation

被引:259
作者
Nothias, Louis-Felix [1 ,2 ,3 ]
Nothias-Esposito, Melissa [3 ,4 ]
da Silva, Ricardo [1 ,2 ]
Wang, Mingxun [1 ,2 ]
Protsyuk, Ivan [5 ]
Zhang, Zheng [1 ,2 ]
Sarvepalli, Abi [1 ,2 ]
Leyssen, Pieter [6 ]
Touboul, David [3 ]
Costa, Jean [4 ]
Paolini, Julien [4 ]
Alexandrov, Theodore [2 ,5 ]
Litaudon, Marc [3 ]
Dorrestein, Pieter C. [1 ,2 ]
机构
[1] Univ Calif San Diego, Collaborat Mass Spectrometry Innovat Ctr, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA
[3] Univ Paris Sud, ICSN UPR 2301, CNRS, Inst Chim Subst Nat, F-91198 Gif Sur Yvette, France
[4] Univ Corsica, UMR SPE 6134, CNRS, Lab Chim Prod Nat, F-20250 Corte, France
[5] EMBL, Heidelberg, Germany
[6] Katholieke Univ Leuven, Rega Inst Med Res, Lab Virol & Expt Chemotherapy, B-3000 Leuven, Belgium
来源
JOURNAL OF NATURAL PRODUCTS | 2018年 / 81卷 / 04期
关键词
MASS-SPECTROMETRY DATA; CHIKUNGUNYA VIRUS; DITERPENE ESTERS; JATROPHANE ESTERS; EUPHORBIA; DEREPLICATION; METABOLOMICS; INTEGRATION; IDENTIFICATION; CHROMATOGRAPHY;
D O I
10.1021/acs.jnatprod.7b00737
中图分类号
Q94 [植物学];
学科分类号
071001 ;
摘要
It is a common problem in natural product therapeutic lead discovery programs that despite good bioassay results in the initial extract, the active compound(s) may not be isolated during subsequent bioassay-guided purification. Herein, we present the concept of bioactive molecular networking to find candidate active molecules directly from fractionated bioactive extracts. By employing tandem mass spectrometry, it is possible to accelerate the dereplication of molecules using molecular networking prior to subsequent isolation of the compounds, and it is also possible to expose potentially bioactive molecules using bioactivity score prediction. Indeed, bioactivity score prediction can be calculated with the relative abundance of a molecule in fractions and the bioactivity level of each fraction. For that reason, we have developed a bioinformatic workflow able to map bioactivity score in molecular networks and applied it for discovery of antiviral compounds from a previously investigated extract of Euphorbia dendroides where the bioactive candidate molecules were not discovered following a classical bioassay-guided fractionation procedure. It can be expected that this approach will be implemented as a systematic strategy, not only in current and future bioactive lead discovery from natural extract collections but also for the reinvestigation of the untapped reservoir of bioactive analogues in previous bioassay-guided fractionation efforts.
引用
收藏
页码:758 / 767
页数:10
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