Journal
CHEMMEDCHEM
Volume 17, Issue 9, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202200113
Keywords
Fragment-based drug discovery (FBDD); Drug design; Library design; Cyclobutane; Three-dimensional (3D)
Categories
Funding
- European Union [675899, 777828]
- Marie Curie Actions (MSCA) [675899] Funding Source: Marie Curie Actions (MSCA)
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Fragment-based drug discovery has a growing need for unique screening libraries. Cyclobutane moiety, identified as an attractive three-dimensional scaffold, was used to synthesize a library of novel 3D cyclobutane fragments. The library exhibited favorable shape and physicochemical properties compared to existing synthetic 3D fragment libraries.
Fragment-based drug discovery (FBDD) has a growing need for unique screening libraries. The cyclobutane moiety was identified as an underrepresented yet attractive three-dimensional (3D) scaffold. Synthetic strategies were developed via a key 3-azido-cyclobutanone intermediate, giving potential access to a range of functional groups with accessible growth vectors. A focused set of 33 novel 3D cyclobutane fragments was synthesised, comprising three functionalities: secondary amines, amides, and sulfonamides. This library was designed using Principal Component Analysis (PCA) and an expanded version of the rule of three (RO3), followed by Principal Moment of Inertia (PMI) analysis to achieve both chemical diversity and high 3D character. Cis and trans ring isomers of library members were generated to maximise the shape diversity obtained, while limiting molecular complexity through avoiding enantiomers. Property analyses of the cyclobutane library indicated that it fares favourably against existing synthetic 3D fragment libraries in terms of shape and physicochemical properties.
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