Lead optimization molecular scaffolds

The molecular shape descriptors presented here are typically of a global nature. They offer ample evidence that shape as a volume or as a surface is an exciting and useful concept when applied to drug discovery. They provide a reliable scaffold for virtual screening and lead optimization by decoration with chemical intuition, but also have their unadorned use as in ligand fitting, prediction, or active site description. 

Langdon, S.R., Ertl, P., and Brown, N. (2010) Bioisosteric replacement and scaffold hopping in lead generation and optimization. Molecular Informatics, 29, 366-385. 

Bioisosteric replacement and scaffold hopping in lead generation and optimization. Molecular Informatics,... 

The systematic exploration of activity cliffs from various representations of activity landscapes is summarized in an interesting article by Stumpfe and Bajorath [79]. These representations could include either distinct chemical transformations (MMPs) or similarity-based relationships between molecules. In a classical medicinal chemistry approach, activity cliffs are extracted from R-group tables, as shown in Figure 10.3 for 3-oxybenzamides as factor Xa inhibitors [58, 59]. This has to be repeated for each scaffold of interest with a predefined view on informative attachment points at the molecular core. Hence this approach is feasible for smaller datasets with only a few informative attachment points for SAR investigation, typically a narrow series in lead optimization. 

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