CSAKD: Determining Absolute Ligand Affinities From ¹⁹F NMR Chemical Shift Anisotropy

Area of Science:

• Medicinal Chemistry
• Biophysics
• Nuclear Magnetic Resonance (NMR) Spectroscopy

Background:

• Small-molecule drug discovery relies on identifying and optimizing initial compound hits.
• Fragment-based drug discovery (FBDD) is a powerful approach, especially when combined with structural and biophysical data.
• Accurately measuring the weak binding affinities of small fragments is a critical challenge in FBDD.

Purpose of the Study:

• To introduce a novel method for determining absolute fragment binding affinities.
• To overcome the limitations of current techniques in quantifying weak fragment interactions.
• To enhance the efficiency and applicability of FBDD workflows.

Main Methods:

• Development of chemical shift anisotropy KD (CSAKD), a method utilizing Fluorine-19 (19F) NMR relaxation.
• Application of CSAKD to determine absolute binding affinities without requiring titration experiments or isotopic labeling.
• Integration with a machine learning model for rapid prediction of 19F chemical shielding tensors.

Main Results:

• CSAKD enables fast and efficient determination of fragment binding affinities.
• The method eliminates the need for laborious titration experiments and costly isotopic labeling.
• The combined approach streamlines affinity determination within FBDD pipelines.

Conclusions:

• CSAKD offers a significant advancement for affinity measurements in FBDD.
• The method provides a rapid, efficient, and label-free approach to quantify fragment binding.
• This technique facilitates the seamless integration of biophysical measurements into early-stage drug discovery.