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Published on: March 3, 2021
Crystalline sponge affinity screening: A fast tool for soaking condition optimization without the need of X-ray
Lara Rosenberger1, Carolina von Essen2, Anupam Khutia2
1Discovery and Development Technologies (DDTech), Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany; Department of Drug Design and Optimization (DDOP), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus E8.1, 66123 Saarbrücken, Germany; Department of Pharmacy, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany.
A new screening method optimizes the crystalline sponge method for small molecule analysis. This technique efficiently identifies ideal soaking conditions, reducing the need for time-consuming X-ray diffraction, and enabling analysis of nanogram quantities.
Area of Science:
- Crystallography
- Analytical Chemistry
- Materials Science
Background:
- The crystalline sponge method is advantageous for structural elucidation of low-quantity small molecules.
- Optimizing guest inclusion requires careful selection of soaking parameters.
- Traditional methods rely on time-consuming X-ray diffraction (XRD) for confirmation.
Purpose of the Study:
- To develop a screening method for optimizing crystalline sponge soaking conditions.
- To reduce reliance on single-crystal XRD for initial parameter selection.
- To enhance the efficiency of structural elucidation for small molecules.
Main Methods:
- A screening assay was developed using 14 test compounds (individual and mixtures).
- Guest soaking was performed under various conditions, followed by solvent evaporation and framework dissolution.
- Liquid chromatography-tandem mass spectrometry (LC-MS/MS) quantified trapped analytes to determine an affinity factor.
- The method was validated by subsequent crystallographic analysis of ten compounds.
Main Results:
- The developed screening method successfully identified optimal soaking parameters.
- An affinity factor, based on analyte amount per crystal size, guided condition selection.
- The method enabled structural analysis of ten compounds with reduced experimental time.
- The lower limit of detection was investigated, with successful determination of analytes using as little as 5 ng of sample.
Conclusions:
- An affinity screening approach can prioritize crystalline sponge soaking parameters efficiently.
- This method significantly reduces the time and resources needed for structural elucidation.
- The crystalline sponge method, enhanced by this screening, is capable of analyzing trace amounts of analytes.
