A genetic algorithm for structure-based de novo design

J Comput Aided Mol Des. 2001 Oct;15(10):911-33. doi: 10.1023/a:1014389729000.


Genetic algorithms have properties which make them attractive in de novo drug design. Like other de novo design programs, genetic algorithms require a method to reduce the enormous search space of possible compounds. Most often this is done using information from known ligands. We have developed the ADAPT program, a genetic algorithm which uses molecular interactions evaluated with docking calculations as a fitness function to reduce the search space. ADAPT does not require information about known ligands. The program takes an initial set of compounds and iteratively builds new compounds based on the fitness scores of the previous set of compounds. We describe the particulars of the ADAPT algorithm and its application to three well-studied target systems. We also show that the strategies of enhanced local sampling and re-introducing diversity to the compound population during the design cycle provide better results than conventional genetic algorithm protocols.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Algorithms*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Cathepsin D / antagonists & inhibitors
  • Cathepsin D / chemistry
  • Drug Design*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Folic Acid Antagonists / chemistry
  • Folic Acid Antagonists / pharmacology
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • Ligands
  • Molecular Structure
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Software
  • Tetrahydrofolate Dehydrogenase / chemistry


  • Anti-HIV Agents
  • Enzyme Inhibitors
  • Folic Acid Antagonists
  • Ligands
  • Protease Inhibitors
  • Reverse Transcriptase Inhibitors
  • Tetrahydrofolate Dehydrogenase
  • HIV Reverse Transcriptase
  • Cathepsin D