Fragment-Based Ligand Discovery Using Protein-Observed

Area of Science:

• Organic Chemistry
• Biophysical Chemistry
• Chemical Education

Background:

• Curriculum-based undergraduate research experiences (CUREs) are increasingly adopted in STEM education.
• CUREs have demonstrated efficacy in improving student retention within STEM disciplines.
• Organic chemistry curricula can benefit from integrating research experiences.

Purpose of the Study:

• To describe a 10-week CURE for a second-semester organic chemistry laboratory.
• To integrate small molecule synthesis with biophysical measurements using protein-observed 19F NMR (PrOF NMR).
• To assess student skill development and self-perceived gains compared to traditional labs.

Main Methods:

• Students performed multistep organic synthesis of small molecules.
• Protein-observed 19F NMR (PrOF NMR) was utilized to determine small molecule binding affinity (Kd) to a target protein.
• Structure-activity relationship (SAR) studies and quantitative biophysical measurements were incorporated.

Main Results:

• The CURE successfully introduced students to organic synthesis, SAR, and quantitative biophysical measurements.
• PrOF NMR experiments provided rapid assessment of ligand-protein binding.
• Student self-perceived skill gains in the CURE surpassed those in traditional and inquiry-based labs.

Conclusions:

• A fragment-based ligand discovery lab using PrOF NMR is readily implementable in undergraduate organic chemistry.
• This CURE enhances scientific literacy and practical skills in biophysical measurements.
• The CURE model shows promise for improving student engagement and retention in chemistry.