Using chiral molecules as an approach to address low-druggability recognition sites

Xavier Lucas, Stefan Günther (Lead / Corresponding author)

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The content of chiral carbon atoms or structural complexity, which is known to correlate well with relevant physicochemical properties of small molecules, represents a promising descriptor that could fill the gap in existing drug discovery between ligand library filtering rules and the corresponding properties of the target's recognition site. Herein, we present an in silico study on the yet unclear underlying correlations between molecular complexity and other more sophisticated physicochemical and biological properties. By analyzing thousands of protein-ligand complexes from DrugBank, we show that increasing molecular complexity of drugs is an approach to addressing particularly low-druggability and polar recognition sites. We also show that biologically relevant protein classes characteristically bind molecules with a certain degree of structural complexity. Three distinct behaviors toward drug recognition are described. The reported results set the basis for a better understanding of protein-drug recognition, and open the possibility of including target information in the filtering of large ligand libraries for screening.

Original languageEnglish
Pages (from-to)2114-2121
Number of pages8
JournalJournal of Computational Chemistry
Volume35
Issue number29
Early online date16 Sep 2014
DOIs
Publication statusPublished - 5 Nov 2014

Keywords

  • Binding sites
  • Carbon
  • Models, Molecular
  • Molecular structure
  • Pharmaceutical preparations
  • Proteins
  • Small molecule libraries
  • Journal article
  • Research support, Non-U.S. Gov't

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