Optimization of antibacterial peptides by genetic algorithms and cheminformatics

Chem Biol Drug Des. 2011 Jan;77(1):48-56. doi: 10.1111/j.1747-0285.2010.01044.x. Epub 2010 Oct 13.


Pathogens resistant to available drug therapies are a pressing global health problem. Short, cationic peptides represent a novel class of agents that have lower rates of drug resistance than derivatives of current antibiotics. Previously, we created a software system utilizing artificial neural networks that were trained on quantitative structure-activity relationship descriptors calculated for a total of 1400 synthetic peptides for which antibacterial activity was determined. Using the trained system, we correctly identified additional peptides with activity of 94% accuracy; active peptides were 47 of the top rated 50 peptides chosen from an in silico library of nearly 100,000 sequences. Here, we report a method of generating candidate peptide sequences using the heuristic evolutionary programming method of genetic algorithms (GA), which provided a large (19-fold) improvement in identification of novel antibacterial peptides. Approximately 0.50% of peptides evaluated during the GA method were classified as highly active, while only 0.026% of the nearly 100,000 sequences we previously screened were classified as highly active. A selection of these peptides was tested in vitro and activities reported here. While GA significantly improves the possibility of identifying candidate peptides, we encountered important pitfalls to this method that should be considered when using GA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms*
  • Amino Acid Sequence / genetics
  • Antimicrobial Cationic Peptides* / chemical synthesis
  • Antimicrobial Cationic Peptides* / genetics
  • Antimicrobial Cationic Peptides* / pharmacology
  • Artificial Intelligence
  • Bacteria / drug effects*
  • Drug Design
  • Inhibitory Concentration 50
  • Microbial Viability / drug effects*
  • Neural Networks, Computer
  • Peptide Library*
  • Quantitative Structure-Activity Relationship


  • Antimicrobial Cationic Peptides
  • Peptide Library