“Escape from Flatland” – New Approach for Scaffold and Library Design. Fsp3 = number of sp3-hybridized carbons/ total carbon count.
Nature is three-dimensional and therefore recognizes small molecules in a complementary 3D-fashion, and so drugs are likely to be more selective for their targets if they are three-dimensional too. Not coincidentally, compounds with diverse and well-developed 3D-shapes have become the most attractive ones on the market of screening compounds for HTS for the last several years. Furthermore, Fsp3 parameter has become one of the most important criterion of HTS libraries value since it was introduced in 2009 by Frank Lovering as a measure of three-dimensionality and therefore complexity for libraries members. According to their findings and our further observations, scaffold/molecule saturation may benefit:
• More diverse set of compounds
• More highly complex molecules
• Natural product-likeness
• Access to greater chemical space
• Better complement to the spatial subtleties of target proteins
• 3D-dimensionality may result in greater selectivity
• Higher water solubility
• Better phys-chemical parameters (logP and PSA)
• Very low increase of MW
• New stereo-centers
As result: Faster transition of compound from discovery to drugs.
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