Computational Bioactivity Fingerprint Similarities to Navigate the Discovery of Novel Scaffolds

Guo Li Xiong, Yue Zhao, Lu Liu, Zhong Ye Ma, Ai Ping Lu, Yan Cheng, Ting Jun Hou*, Dong Sheng Cao*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

13 Citations (Scopus)


As one of the central tasks of modern medicinal chemistry, scaffold hopping is expected to lead to the discovery of structural novel biological active compounds and broaden the chemical space of known active compounds. Here, we report the computational bioactivity fingerprint (CBFP) for easier scaffold hopping, where the predicted activities in multiple quantitative structure–activity relationship models are integrated to characterize the biological space of a molecule. In retrospective benchmarks, the CBFP representation shows outstanding scaffold hopping potential relative to other chemical descriptors. In the prospective validation for the discovery of novel inhibitors of poly [ADP-ribose] polymerase 1, 35 predicted compounds with diverse structures are tested, 25 of which show detectable growth-inhibitory activity; beyond this, the most potent (compound 6) has an IC50 of 0.263 nM. These results support the use of CBFP representation as the bioactivity proxy of molecules to explore uncharted chemical space and discover novel compounds.

Original languageEnglish
Pages (from-to)7544-7554
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number11
Publication statusPublished - 10 Jun 2021

Scopus Subject Areas

  • Molecular Medicine
  • Drug Discovery


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