High throughput solubility determination with application to selection of compounds for fragment screening

Design of compound libraries for fragment screening

“…The need for good aqueous solubility was seen as particularly critical for this screening methodology and only those compounds with molecular weight below 200 Da and ClogP less than 2 were included in the X-ray library. It is important to note that this work pre-dated the availability of shape fingerprinting methodology [46] and the measured solubility data [18] that were used in the design of GFSL05 and APGNMR07.…”

“…Solubility is favored by low lipophilicity and the presence of ionizable groups in the molecule although, as noted in the introduction, excessively polar fragments are less likely to bind to screening targets. We have used measurements from a high-throughput solubility assay to model the risk of selecting poorly soluble fragments as a function of ClogP [18] and to check the solubility of more lipophilic compounds before including these in the library. Once the initial analysis has been carried out, solubility was only measured for neutral compounds with ClogP of at least 2.2 and the measured values were required to exceed the upper limit of 100 mM for the assay.…”

“…Measurements were made for neutral compounds with ClogP greater than 2.2, which were predicted to have an unacceptable risk of poor aqueous solubility [18].…”

“…Low lipophilicity and the presence of ionizable groups both favor aqueous solubility although analysis showing that hits from NMR screens are more lipophilic than non-hits suggests that minimization of lipophilicity is a poor strategy for library design [4]. Approaches to managing the risk of selecting poorly soluble fragments have been described [18].…”

Interpreting physicochemical experimental data sets

“…Aqueous solubilities can be measured by numerous methods including shake-flask with separation and quantification of the supernatant by ultraviolet-visible (UV) spectroscopy [2][3][4][5][6], liquid chromatography (LC) UV [6][7][8], or LC tandem mass spectroscopy (MSMS) [7], turbidimetric methods [9][10][11] or potentiometric approaches [12,13].…”