title: On the origins of three-dimensionality in drug-like molecules.
abstract: Many medicinal chemistry-relevant structures and core scaffolds tend toward geometric planarity, which hampers the optimization of physicochemical properties desirable in drug-like molecules. As challenging drug target classes emerge, the exploitation of molecular three-dimensionality in lead optimization is becoming increasingly important. While recent interest has emphasized the importance of enhanced three-dimensionality in molecular fragment designs, the extent to which this is required in core scaffolds remains unclear.
  
  
  
  Three computational methods, Scaffold Tree deconstruction, Synthetic Disconnection Rules retrosynthetic deconstruction and virtual library enumeration, are applied, together with the descriptors plane of best fit and principal moments of inertia, to investigate the origins of three-dimensionality in drug-like molecules.
  
  
  
  This study informs on the stage at which molecular three-dimensionality should be considered in drug design.
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK.
authors: Joshua
authors: J
authors: Meyers
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK.
authors: Michael
authors: M
authors: Carter
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK.
authors: N Yi
authors: NY
authors: Mok
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK.
authors: Nathan
authors: N
authors: Brown
mesh_terms: D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D004364:Pharmaceutical Preparations; D054852:Small Molecule Libraries
keywords: drug-like molecules; library enumeration; molecular shape; molecular three-dimensionality; plane of best fit; principal moments of inertia; scaffolds; ternary density plots