This printable "enzyme" with multiple target sites is designed to teach students the basics of small molecule drug design as well as serve as an introduction to using basic CAD design software to build 3D-printable objects. The enzyme has multiple active sites and surface binding sites. Students will download the STL file into a program such as Tinkercad and will use the CAD software to design "molecules" that could fit into the target sites and block the enzyme from binding to its normal small molecules. The model includes sites for competitive and non-competitive inhibition of the enzyme. One of the noncompetitive sites, when a "drug molecule" binds to it, closes off an active site (see pictures) to demonstrate how allosteric binding can change the structure of the enzyme.
Once students design molecules that can inhibit the protein, the models can be printed and tested with the the printed enzyme. Successful small molecule drugs should fit snugly into the target sites. In this process, the students will also learn strategies for successful printing and how/when to use infill, rafts, and supports.
Once printed, students can compare the different solutions to the same target sites, leading to a discussion of how many drugs for the same problem bind to the same site but have slightly different structures (i.e. Claritin and Zyrtec for allergies). The advantages and disadvantages of these slight differences (such as half-life in the body and side-effects) can be discussed.
Lastly, students can connect their designs to molecular geometry by trying to recreate their drug designs using the basic shapes that molecules can form. This will then lead to a discussion of the real-world process of drug design.

Pharmaceutical chemistry is a fun way to get students interested in learning about molecular biology and proteins. In this activity, students will learn about inhibitors and how scientists design molecules that will fit into active sites or surface sites on proteins.

Preparation:

Students should already be familiar with enzymes, active sites, and the basics of competitive and noncompetitive inhibition. They should have a basic understanding of protein structure and the importance of this structure in relation to function.

Optionally, students may be given an introduction to using basic CAD software such as Tinkercad or 123D Design. The activity can be used as an exploration though to learn how to use these pieces of software themselves. During the activity, students may need guidance on how to best design the pieces for easy printing.

Objectives:

Students will be able to explain the difference between competitive and noncompetitive (allosteric) inhibitors.

Students will be able to describe how small molecule drugs can be designed to act as inhibitors.

Students will be able to design 3D-printable shapes in CAD.

Students will be able to connect molecular geometry to enzyme target site shapes.

Students will be able to describe the process by which real world drugs are designed.

After students have been introduced to the idea of enzymes, active sites, inhibitors, and the use of small molecule drugs as inhibitors (provide a few real world examples such as allergy medicines, pain relievers, and antibiotics), introduce the drug design activity. Students will download the enzyme STL file and open it in a CAD program such as Tinkercad or 123D Design. They will then use the software to design "small molecule drugs" that would fit snuggly into the various active sites and allosteric binding sites on the enzyme. Assist students as needed in using the chosen software. Students should attempt to design small molecules for as many sites as possible. (Optional: assign a point system to the various target sites to turn the activity into a game. Once the small molecule drugs are printed, the student with the most points wins).
Once the students have made their designs, instruct students on how a 3D printer works and how to best position their designs for printing as well as how to minimize the material used. Guide them through the use of a basic slicing program as well and then print the designs. (Any designs that fail to print can be used as teachable moments as to what works and does not work in 3D printing).
Once printed, check to see which designs were successful by seeing which fit well into the various active sites on the printed enzyme. Discuss how different students have created slightly different designs for the same target sites. Compare to different brands of drugs for the same problem such as Claritin and Zyrtec for allergies. These drugs have similar shapes and target sites but have slightly different side-effects and half-lifes in the body. Have students try to recreate the shapes of the small molecules that they made using molecular geometries. Model kits can be used if available to help students visualize these shapes. Once students have made these designs discuss the next steps in the drug design process as they have reached the point of creating multiple real drug candidates. The discussion should include the steps in drug testing, packaging the drug, and human trials.