A practical drug discovery project at the undergraduate level

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Undergraduate Education

Background:

• A weakly potent and insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (compound 1) was selected as a starting point.
• No prior medicinal chemistry knowledge was required for student participation.

Purpose of the Study:

• To provide third-year undergraduates with a practical drug discovery experience.
• To simulate real-life industrial drug development processes.
• To improve the potency and aqueous solubility of a lead PI3Kδ inhibitor.

Main Methods:

• Students worked in teams, applying principles from initial lecture workshops.
• Methods included compound array design, molecular modeling, and screening data analysis.
• Laboratory synthesis of 48 target compounds was performed with industrial support.

Main Results:

• The best synthesized compounds (5b, 5j, 6b, 6ap) demonstrated significant improvements over the lead compound (1).
• Potency was enhanced 100-1000 fold.
• Aqueous solubility was increased by at least tenfold.

Conclusions:

• The project successfully enhanced the inhibitor's profile, achieving substantial improvements in potency and solubility.
• The learning experience closely mirrored industrial drug discovery practices.
• Significant industrial collaboration facilitated the project's success and provided valuable mentorship.