De novo design of multitarget ligands with an iterative fragment-growing strategy

Erchang Shang, Yaxia Yuan, Xinyi Chen, Ying Liu, Jianfeng Pei, Luhua Lai

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


The discovery of multitarget drugs has recently attracted much attention. Most of the reported multitarget ligands have been serendipitous discoveries. Although a few methods have been developed for rational multitarget drug discovery, there is a lack of elegant methods for de novo multitarget drug design and optimization, especially for multiple targets with large differences in their binding sites. In this paper, we report the first de novo multitarget ligand design method, with an iterative fragment-growing strategy. Using this method, dual-target inhibitors for COX-2 and LTA4H were designed, with the most potent one inhibiting PGE2 and LTB4 production in the human whole blood assay with IC50 values of 7.0 and 7.1 μM, respectively. Our strategy is generally applicable in rational and efficient multitarget drug design, especially for the design of highly integrated inhibitors for proteins with dissimilar binding pockets.

Original languageEnglish (US)
Pages (from-to)1235-1241
Number of pages7
JournalJournal of Chemical Information and Modeling
Issue number4
StatePublished - Apr 28 2014
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences


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