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Author Spotlight: Unveiling the Structural and Dynamic Aspects of Glycan Molecular Recognition

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1D and 2D NMR for KRAS:Ligand Binding.

Gabriel Cornilescu¹

¹NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. gabriel.cornilescu@nih.gov.

Methods in Molecular Biology (Clifton, N.J.)

|April 3, 2024

Summary

Nuclear Magnetic Resonance (NMR) methods enable drug discovery by screening fragment binding to oncogenic KRAS mutants. These techniques assess compound interactions and protein states, aiding in the development of targeted therapies.

Keywords:

CSP FBDD FBS HSQC titration KRAS NMR screening STD WaterLOGSY

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Area of Science:

Biochemistry
Structural Biology
Drug Discovery

Background:

Fragment-based screening and binding interface mapping are crucial in drug discovery.
Nuclear Magnetic Resonance (NMR) spectroscopy offers powerful tools for analyzing molecular interactions.

Purpose of the Study:

To apply ligand-observed 1D NMR and protein-observed 2D NMR for fragment screening.
To map binding interfaces of small molecules to oncogenic KRAS mutants.

Main Methods:

Utilized 1D NMR for fragment screening and affinity assessment.
Employed 2D NMR for binding interface mapping and protein analysis.
Investigated both active (GMPPNP-bound) and inactive (GDP-bound) states of KRAS.

Main Results:

Demonstrated the capability of NMR methods to detect compound binding across a wide affinity range.
Showcased simultaneous assessment of compound properties (solubility, purity, formula accuracy) and protein integrity.
Successfully applied these NMR techniques to oncogenic KRAS mutants.

Conclusions:

NMR-based fragment screening and binding mapping are effective for drug discovery targeting KRAS.
These methods provide comprehensive data for evaluating fragment leads and understanding target engagement.