Enzyme Inhibitor Drug Design Activity

myminifactory

This interactive "enzyme" with numerous target sites is designed to teach students the basics of small molecule drug development while introducing them to basic CAD design software for building 3D-printable objects. The enzyme features multiple active sites and surface binding sites. Students will download the STL file into a program such as Tinkercad, then use CAD software to create "molecules" that fit snugly into target sites and block the enzyme from binding with its normal small molecules. The model includes sites for competitive and non-competitive inhibition of the enzyme. One non-competitive site closes off an active site when a "drug molecule" binds to it, illustrating how allosteric binding can alter the enzyme's structure. Students will design molecules that inhibit proteins, then print and test the printed enzymes with their designs. Successful small molecule drugs fit snugly into target sites. In this process, students also learn strategies for successful printing and when/where to use infill, rafts, and supports. Once printed, students can compare 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 (e.g., 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. Students will then connect their designs to molecular geometry by recreating their drug designs using basic shapes that molecules form, leading to a discussion of the real-world process of drug development. Pharmaceutical chemistry is an engaging way to get students interested in learning about molecular biology and proteins. In this activity, students learn about inhibitors and how scientists design molecules that fit into active sites or surface sites on proteins. Preparation: * Students should already be familiar with enzymes, active sites, competitive inhibition, non-competitive (allosteric) inhibition, protein structure, and the importance of structure in relation to function. * Optionally, students may receive an introduction to using basic CAD software such as Tinkercad or 123D Design. The activity can serve as a hands-on exploration to learn how to use these pieces of software themselves. During the activity, students may need guidance on designing pieces for easy printing. Objectives: * Students will explain the difference between competitive and non-competitive (allosteric) inhibitors. * Students will describe how small molecule drugs are designed to act as inhibitors. * Students will design 3D-printable shapes in CAD. * Students will connect molecular geometry to enzyme target site shapes. * Students will describe the process by which real-world drugs are designed. After introducing students to enzymes, active sites, inhibitors, and the use of small molecule drugs as inhibitors (provide a few 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 CAD software like Tinkercad or 123D Design. They will then use the software to create "small molecule drugs" that fit snugly into 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 target sites to turn the activity into a game). Once designs are made, instruct students on how 3D printing works and how to position their designs for printing while minimizing material used. Guide them through a basic slicing program and then print the designs (Any designs that fail to print can be used as teachable moments about what works and does not work in 3D printing). Once printed, check 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 these designs 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-lives in the body. Have students try to recreate the shapes of their small molecules 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 drug development 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.