Descriptor-free molecular discovery in large libraries by adaptive substituent reordering

Scott R. McAllister, Xiao Jiang Feng, Peter A. DiMaggio, Christodoulos A. Floudas, Joshua D. Rabinowitz, Herschel Rabitz

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Molecular discovery often involves identification of the best functional groups (substituents) on a scaffold. When multiple substitution sites are present, the number of possible substituent combinations can be very large. This article introduces a strategy for efficiently optimizing the substituent combinations by iterative rounds of compound sampling, substituent reordering to produce the most regular property landscape, and property estimation over the landscape. Application of this approach to a large pharmaceutical compound library demonstrates its ability to find active compounds with a threefold reduction in synthetic and assaying effort, even without knowing the molecular identity of any compound.

Original languageEnglish (US)
Pages (from-to)5967-5970
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Issue number22
StatePublished - Nov 15 2008

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Molecular Medicine
  • Molecular Biology
  • Biochemistry
  • Clinical Biochemistry
  • Pharmaceutical Science
  • Organic Chemistry


  • Combinatorial library
  • Global optimization
  • Iterative operation
  • Molecular discovery
  • QSAR
  • Substituent reordering


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