Combinatorial chemistry as a tool for drug discovery

Prog Med Chem. 1999;36:91-168. doi: 10.1016/s0079-6468(08)70046-8.


The question 'will combinatorial chemistry deliver real medicines' has been posed [96]. First it is important to realise that the chemical part of the drug discovery process cannot stand alone; the integration of synthesis and biological assays is fundamental to the combinatorial approach. The results presented in Tables 3.1 to 3.8 suggest that so far smaller directed combinatorial libraries have obtained equivalent results to those obtained previously from traditional medicinal chemistry analogue programs. Unfortunately, because of the long time it takes to develop pharmaceutical drugs there are no examples yet of marketed drugs discovered by combinatorial methods. There are interesting examples where active leads have been discovered from the screening of the same library against multiple targets (e.g. libraries 13, 39, 43, 66, 71 and 76). It is now possible to handle much larger libraries of non-oligomeric structures and the chemistry required for such applications is becoming available. Whether combinatorial approaches can also be adapted to deal with all the other requirements of a successful pharmaceutical (lack of toxicity, bioavailability etc.) is open to question but there are already examples such as cassette dosing [235-237]. However we can still be optimistic about the possibility of larger libraries producing avenues of investigation for the medicinal chemist to develop into real drugs. Combinatorial chemistry is an important tool for the medicinal chemist.

Publication types

  • Review

MeSH terms

  • Combinatorial Chemistry Techniques*
  • Drug Evaluation, Preclinical / methods*
  • Enzyme Inhibitors / chemistry
  • Humans
  • Peptide Library
  • Protease Inhibitors / chemistry
  • Receptors, Drug / antagonists & inhibitors


  • Enzyme Inhibitors
  • Peptide Library
  • Protease Inhibitors
  • Receptors, Drug