A practical drug discovery project at the undergraduate level

• Published in: Drug discovery today 2013-12, Vol.18 (23-24), p.1158-1172
• Main Authors: Jonathan Fray, M., Macdonald, Simon J.F., Baldwin, Ian R., Barton, Nick, Brown, Jack, Campbell, Ian B., Churcher, Ian, Coe, Diane M., Cooper, Anthony W.J., Craven, Andrew P., Fisher, Gail, Inglis, Graham G.A., Kelly, Henry A., Liddle, John, Maxwell, Aoife C., Patel, Vipulkumar K., Swanson, Stephen, Wellaway, Natalie
• Format: Article
• Language: English
• Subjects: Chemistry, Pharmaceutical - education; Class Ia Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Curriculum; Drug Design; Drug Discovery - methods; Drug Industry - methods; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Models, Molecular; Solubility
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2013.09.004

•We describe a practical drug discovery project for undergraduates.•The project aims to mimic real-life drug discovery.•Students design and make target compounds in teams.•The focus is to balance potency, lipophilicity and solubility.•We extend the published structure-activity relationships of PI3Kδ inhibitors. In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100–1000 fold and ≥tenfold, respectively. ‘You make the compounds you design’: this article describes a new way for chemistry undergraduates to learn about drug discovery.