Fragments typically have to be screened at high concentration because they normally only bind weakly to their targets and the physicochemical property most relevant to FBDD is aqueous solubility. Both charge state and lipophilicity influence solubility in aqueous media.
General
Avdeef, Physicochemical profiling (solubility, permeability, and charge state). Curr. Top. Med. Chem. 2001, 1, 277-351 Link
Hydrogen bonding
Kenny, Hydrogen bonding, electrostatic potential, and molecular design. J. Chem. Inf. Model. 2009, 49, 1234-1244 DOI
Laurence & Berthelot, Observations on the strength of hydrogen bonding. Perspect. Drug Discov. Des. 2000, 18, 39-60 DOI
Kenny, Prediction of hydrogen bond basicity from computed molecular electrostatic properties: implications for comparative molecular field analysis. J. Chem. Soc., Perkin Trans. 2, 1994, 199-202 DOI
Abraham et al, Hydrogen bonding. Part 9. Solute proton donor and proton acceptor scales for use in drug design. J. Chem. Soc., Perkin Trans. 2, 1989, 1355-1375 DOI
Partition coefficients
Toulmin et al, Toward Prediction of Alkane/Water Partition Coefficients. J. Med. Chem. 2008, 51, 3720-3730 DOI
Leahy et al, Model solvent systems for QSAR. Part 2. Fragment values (f-values) for the critical quartet. J. Chem. Soc., Perkin Trans. 2, 1992, 723-731 DOI
Solubility
Colclough et al, High throughput solubility determination with application to selection of compounds for fragment screening. Bioorg. Med. Chem. 2008, 16, 6611-6616 DOI
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