Rational design of macrolides by virtual screening of combinatorial libraries generated through in silico manipulation of polyketide synthases

J Med Chem. 2006 Mar 23;49(6):2077-87. doi: 10.1021/jm051035i.


Bacterial secondary metabolites display diverse biological activities, thus having potential as pharmacological agents. Although most of these compounds are discovered by random screening, it is possible to predict and re-design their structures based on the information on their biosynthetic pathways. Biosynthesis of macrolides, governed by modular polyketide synthases (PKS), obeys certain rules, which can be simulated in silico. PKS mode of action theoretically allows for a huge number of macrolides to be produced upon combinatorial manipulation. Since engineering of all possible PKS variants is practically unfeasible, we created Biogenerator software, which simulates manipulation of PKS and generates virtual libraries of macrolides. These libraries can be screened by computer-aided prediction of biological activities, as exemplified by analysis of erythromycin and macrolactin libraries. This approach allows rational selection of macrolides with desired biological activities and provides instructions regarding the composition of the PKS gene clusters necessary for microbial production of such molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Combinatorial Chemistry Techniques*
  • Computer Simulation
  • Databases, Factual*
  • Drug Design
  • Erythromycin / analogs & derivatives
  • Erythromycin / chemistry
  • Glycosylation
  • Hydroxylation
  • Macrolides / chemistry*
  • Multigene Family
  • Oxidation-Reduction
  • Polyketide Synthases / chemistry*
  • Polyketide Synthases / genetics
  • Quantitative Structure-Activity Relationship
  • Software


  • Macrolides
  • macrolactin A
  • Erythromycin
  • Polyketide Synthases