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Fragment Library with Experimental Solubility

Solubility is defined as one of the essential physicochemical properties of drug candidates. Its measurement is critical in the in vitro profiling of drug-like properties. An early assessment of solubility in drug discovery projects provides valuable insights for better interpretation of screening results and the design of new molecules.

Low aqueous solubility of compounds can bring about misleading outcomes during functional assays, thus, increasing the risk of obtaining false hits or leads. Furthermore, these compounds tend to bind strongly to plasma proteins, resulting in poor tissue distribution and a higher potential for CYP enzyme inhibition. By measuring solubility at the early stages of drug discovery, we can identify potentially ambiguous activity data, such as false negatives caused by low solubility, thus improving the overall quality of activity screening and hit identification efficiency.

Recognizing the significance of solubility in fragment-based drug discovery (FBDD) screening techniques, the Life Chemicals team has developed an in-house high-throughput method for determining the kinetic and thermodynamic aqueous solubility of fragments from its proprietary Fragment Compound Collection [1-7].

We are offering more than 27,600 readily available fragments with confirmed DMSO and aqueous solubility. In addition, over 10,500 fragments soluble at high concentrations have been included in our High Solubility Fragment Subset.

Each compound in the Library is labeled with its corresponding solubility measurement method. We regularly update and expand this Fragment Library, striving to add newly synthesized compounds that undergo rigorous filtering based on physicochemical and structural parameters.

The compound selection can be customized based on your requirements. Cherry picking is available.

Please, contact us at orders@lifechemicals.com for any additional information and price quotations.

For a pre plated set based on this Screening Library, please, search our Pre-plated Fragment Screening Sets.

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DMSO solubility measurement

The procedure includes visual determination of solubility by observing scattering of solutions at different concentrations in DMSO, and the results are presented as DMSO solubility intervals:

  • ≥ 200 mM
  • < 200 mM ≥ 100 mM
  • < 100 mM ≥ 50 mM
  • < 50 mM ≥ 20 mM

The amount and examples of compounds soluble in DMSO in different concentrations.

Figure 1. The amount and examples of compounds soluble in DMSO in different concentrations.

Thermodynamic Experimental Solubility Data in PBS

Almost 16,800 fragments possess experimental thermodynamic solubility data in PBS (Phosphate Buffer Saline) at pH = 7.4. The procedure includes quantity measurement of solubility, using HPLC for a compound solution at varying concentrations (up to 200 mM) in PBS. [7]

Note: Solubility results obtained by this method can be different from similar kinetic solubility measurements, where DMSO was used as a co-solvent, which may exponentially increase compound solubility.

Violin plot of compounds solubility in PBS and examples of their structures.

 

Figure 2. Violin plot of compounds solubility in PBS and examples of their structures.

 

Kinetic Experimental Solubility Data in PBS

The procedure includes visual determination of solubility by observing the scattering of solutions under the following conditions:

  • 5 mM in phosphate buffer with 2.5 % DMSO
  • 1 mM in phosphate buffer with 0.5 % DMSO

This value is measured for approximately 12,000 compounds, mainly from the Life Chemicals Advanced Fragment Library. Approximately 81 % of these fragments are soluble in phosphate buffer at 1 mM and 66 % – at 5 mM.

High Solubility Fragment Subset

All compounds included in the High Solubility Fragment Subset (10,500 fragments) possess minimum experimentally confirmed solubility in PBS at 1 mM and in DMSO at 200mM, measured by the thermodynamic method using HPLC.

Representative Fragments with Experimental Solubility Data

References

  1. Avdeef, A., C.M. Berger, and C. Brownell, pH-metric solubility. 2: correlation between the acid-base titration and the saturation shake-flask solubility-pH methods. Pharmaceutical research, 2000. 17(1): p. 85-89.
  2. Avdeef, A., Solubility, in Absorption and Drug Development2012, John Wiley & Sons, Inc. p. 251-318.
  3.  Alsenz, J. and M. Kansy, High throughput solubility measurement in drug discovery and development. Advanced drug delivery reviews, 2007. 59(7): p. 546-567.
  4. Hoelke, B., et al., Comparison of nephelometric, UV-spectroscopic, and HPLC methods for high- throughput determination of aqueous drug solubility in microtiter plates. Analytical chemistry, 2009. 81(8): p. 3165-3172.
  5. Tihanyi, K. and M. Vastag, Solubility, delivery and ADME problems of drugs and drug- candidates2011: Bentham Science Publishers.
  6. Valko, K., Physicochemical and biomimetic properties in drug discovery: chromatographic techniques for lead optimization 2013: John Wiley & Sons.
  7. Pitt, A., High-throughput screening to determine aqueous drug solubility: the author describes an aqueous solubility screening assay methodology that uses 96-well plates and compares performance to the conventional shake-flask method. Pharmaceutical Discovery, 2005. 5(1): p. 46-50.
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