In Vitro Binding of Platinum Anticancer Drugs to DNA Observed Directly by Polyacrylamide Gel Electrophoresis : A Multiweek Undergraduate Laboratory Investigation (Journal Article)

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Abstract: Structure–activity relationships are foundational concepts in biochemistry and drug design. Despite their importance, it can be difficult to create and execute laboratory activities that allow students to directly observe the interactions between small-molecule drugs and their biomolecular targets. Here, we report an activity that investigates the binding of well-known platinum drugs to short, double-stranded DNA hairpin structures. Students chose multiple Pt drugs to investigate, along with one or more different experimental conditions, performed the Pt–DNA binding reactions, and then characterized the samples by denaturing polyacrylamide gel electrophoresis. Then, they rationalized their gel data on the basis of the structures of the Pt drugs and of double-stranded DNA. In addition to experimentally observing Pt–DNA interactions, students used molecular visualization software to identify other drug interactions with nucleic acids using structures obtained from the Protein Data Bank to determine their mode of binding. The activity was performed by upper-level undergraduate biochemistry students over 3 weeks and uses inexpensive equipment commonly found in any standard undergraduate biochemistry teaching laboratory. It affords an excellent opportunity for students to manipulate and characterize macromolecular structures and directly connect these experimental observations to important concepts in drug chemistry, bioinorganic chemistry, and chemical biology.