Biased and unbiased strategies to identify biologically active small molecules

Bioorg Med Chem. 2014 Aug 15;22(16):4474-89. doi: 10.1016/j.bmc.2014.04.019. Epub 2014 Apr 21.


Small molecules are central players in chemical biology studies. They promote the perturbation of cellular processes underlying diseases and enable the identification of biological targets that can be validated for therapeutic intervention. Small molecules have been shown to accurately tune a single function of pluripotent proteins in a reversible manner with exceptional temporal resolution. The identification of molecular probes and drugs remains a worthy challenge that can be addressed by the use of biased and unbiased strategies. Hypothesis-driven methodologies employs a known biological target to synthesize complementary hits while discovery-driven strategies offer the additional means of identifying previously unanticipated biological targets. This review article provides a general overview of recent synthetic frameworks that gave rise to an impressive arsenal of biologically active small molecules with unprecedented cellular mechanisms.

Keywords: Diversity-oriented synthesis; Drug discovery; Dynamic combinatorial chemistry; Fragment-based drug discovery; In situ click chemistry.

Publication types

  • Review

MeSH terms

  • Animals
  • Click Chemistry
  • Combinatorial Chemistry Techniques
  • Drug Discovery*
  • Humans
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*


  • Small Molecule Libraries