Science Buddies: "Ask an Expert"

Hello,

My name is Renee Daciuk and I am a first-year researcher. I am currently part of Science Research at my school and I have a project, however need help with certain aspects in my project.

I am basing my project off of one on ScienceBuddies, however will be using my own protein and virus.

First, let me introduce my project below.

Influenza A is an acute viral strain of the respiratory tract that causes the most severe clinical disease and is the commonest cause of seasonal epidemics and pandemics in human populations. The virus entry process utilizes the two viral proteins neuraminidase and hemagglutinin to bind to the sialic acid receptor found on the surfaces of glycoproteins and gangliosides. A specific glycoprotein found ubiquitously in the respiratory tract is known as MUC4, a member of the transmembrane mucin family. It is expressed in airway epithelial cells and body fluids and contains sialic acid receptors that the virus attaches to in order to infect the epithelial cells. Anti-viral drugs that can block infection by binding the MUC4 protein can prevent binding of the Influenza virus to these epithelial cells. However, the untested drugs might interfere with important signaling pathways and functions of the MUC4 protein. By using bioinformatics tools to explore which functions of MUC4 and non-target proteins related to MUC4 are affected, we will be able to use the results of this experiment to prevent the drug from interfering with normal cellular and bodily functions.

My project is very similar to a project investigating the effects of drugs on the function of NPC1, a protein used by the Ebola virus. Background information on this project is linked below.
https://www.sciencebuddies.org/science- ... background

However, additionally I will attempt to design a hypothetical, virtual 3D model of a drug that could bind to the protein in order to provide a better view on the drug that would then attach to MUC4 to prevent viral infection. My current struggle is finding the specific way or procedure on how to design this virtual 3D model of the drug, which I wanted to be similar to the viral glycoprotein hemagglutinin, which binds to the MUC4 protein from the virus.

I looked into Homology Modeling, but I am not sure if it is the right method to use, as I do not have a "target" sequence, because I am essentially designing a completely new drug that will behave closely to hemagglutinin.

I am new to designing these models and am urgently trying to find a procedure or method to use to design this 3D model. Although the model does not need to be super specific and tested yet, as I do not have access to drug-testing materials and am simply trying to build a hypothetical structure of a drug, any advice or help to guide me along this project would be incredibly helpful.

Thank you so much,
Renee Daciuk

Hello!

This is a really interesting project! If you used hemagglutinin as your target sequence for homology modeling, then it would show you structures of other proteins that are similar to it. As you said, that probably wouldn’t suit your needs since you’re trying to design a new drug. To design your own drug, I would start by looking at a 3D model of hemagglutinin on Influenza A. Here’s a link to a 3D model that you can look at. Since the sialic acid on the hemagglutinin is binding to sialic acid receptors on MUC4, you can scroll down on the page and look at the chemical structure for the sialic acid branch on this particular hemagglutinin molecule. Try to figure out where on the MUC4 protein the sialic acid would bind.

https://www.rcsb.org/structure/4QY1

The key to designing this drug would be to make it bind to MUC4 more strongly than the influenza virus does so the drug can outcompete the virus. Here are some links to online resources that talk about the drug design process and the chemistry behind how drugs bind to their targets. Using these resources, you might be able to redesign the amino acid sequence at the MUC4 binding site on the hemagglutinin to make it bind to MUC4 more strongly than normal hemagglutinin would. The first link takes you to a website where you can practice designing your own drug molecules.

http://www.drug-design-workshop.ch/home.php

https://pubs.acs.org/doi/full/10.1021/a ... ed.6b00596

https://sites.duke.edu/thepepproject/mo ... chemistry/

I’m definitely not an expert on drug design, so another Expert may chime in with more information, but I hope these resources can help get you started!

Katelyn