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Introduction to molecule drug discovery

Introduction to drug discovery
Hello! Welcome to this course! What is the topic we will discuss today? Today we will introduce you how to identify and optimize a molecule drug. Drug discovery is always important. It can help us to against some serious diseases such as cancers, diabetes, and bacterial infections. You are right, it’s the reason why we need to improve the drug discovery efficiency. Currently, many field are cooperate to reduce the developmental period of a new drug. This field includes chemistry, biology, bioinformatics, molecular biology, and structural biology. In particular, structural biology wasn’t used to facilitate the drug design until recently. What is structural biology?
Structural biology focuses on obtaining and analyzing the 3D information of marker molecules which not only includes structures of proteins and nucleic acid, but also their biological functions and body mechanisms with other molecules. This information provides variable guidance to the design of inhibitors. Sounds good! Will we discuss structural biology today? Sure, this is an important issue in the process of drug design today. We should give an example of new recently drug design to students. How about the epidermal growth factor receptor? The epidermal growth factor receptor is highly associated with lung cancer and has been considered as a good target for drug design. Sounds good! Let’s do it! Lets introduce the epidermal growth factor receptor first. Sounds great!
But how can we reach it? Don’t worry! We will use the movie to introduce the flowchart of the EGFR drug design Let’s go! This video shows the workflow of the structures drug design approach to develop new drugs for a disease. There are several steps in the drug design process as shown by the arrows. They are target selection, hit identification, lead optimization, experimental validation, and clinical trials. Here, non-small cell lung cancer is used as an example to demonstrate these steps. The selected target is epidermal growth factor receptor or EGFR, which is often over-expressed in non-small cell lung cancer.
Normally, it plays a critical role in many biological processes, but when it is over expressed, it triggers signal pathways leading to tumor growth progression and resistance to chemotherapy and radiation treatments. When EGFR switch is turned on, uncontrolled growth and spread of tumor are resulted, which becomes a gateway to disease.
Therefore, EGFR is chosen as a therapeutic target for lung cancer.
The intracellular domain is a tyrosine kinase, that transfers the phosphate group from ATP to to tyrosine residues of protein substrates. This is the structure of EGFR intracellular tyrosine kinase domain. The following steps shows the process of identifying small molecules to inhibit the EGFR activity. The active site is represented by thin lines. To identify EGFR inhibitions, virtual screening is first performed to discover the potential candidates followed by experimental verification of activity. In virtual screenings, compounds are docked into the active site using molecular docking tools, such as iGEMDOCK. Compounds that cannot bind the side well are less likely to be inhibitors and are filtered out.
This compound, N-phenylquinazolin- 4-amine, forms the actions with the active site and thus is selected to test the activity by experiments. Its IC50 value is 344 nM. In the lead optimization step, two functional groups are attached to the compound for enhancing activity, (IC50) 29 nM. Again, another functional group is attached to the additional interactions with the residues of the active site. The final compound, Gefitinib or Iressa inhibits EGFR with an IC50 value of less than or equalling 23 nM. The compound prevents the binding of ATP by occupying the active site. Thus, in this step, the activity of the compound is improved from 344 nM to 23 nM or less than that.
The compound is then validated by experiments including cell based assay and animal testing.
Finally, the compound is submitted to clinical trials to treat EGFR overexpressing diseases. If the clinical trials are successful, the compounds becomes a new drug approved for treating lung cancer.
From this movie, you may have some concepts of drug design, you can find more detailed information in our lectures. Please enjoy it! Bye bye!

Welcome to Week 4. This week we will talk about how to identify and optimize a molecule drug.

Drug discovery is a huge topic. Instead, we will use several cases to demonstrate how a drug is discovered. You will learn the basics of epidermal growth factor (EGF) and its receptor, EGFR. Also, you will learn about the current development of EGFR-related drugs.

Educators of this week:

Prof. Hao-Ching Wang
Prof. Che-Chang Chang
Prof. Hsu Kai-Cheng

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