BIOM 200 From the Molecule to the Organism
Laboratory Exercise October 30, 2006
Instructor: Prof . Philip E. Bourne, firstname.lastname@example.org
These notes can be found at http://www.sdsc.edu/pb/edu/biom200
This follows the lecture on protein-protein and protein-ligand interactions from the point of view of how a pharmaceutical compound interacts with its target. We will review several internet resources with the goal of better understanding the molecular basis of the interaction, the target and the drug. We will consider two examples:
We will work through 1 together and you will then work individually, using the same resources to better understand 2.
Take home message: You have a reference to a process from which to exam any protein ligand interaction using Web resources.
1. – Finding and understanding structures which have Indinavir bound
Go to the Protein Data Bank the source of all publicly accessible macromolecular structures. Enter Indinavir into the text box. The result is 3 tabs – Structure Hits, Unreleased Structures and Web Page Hits - select the Web Pages tab and learn what you can from the entries. What have you learnt about the mode of action of this drug?
Now select the Structure Hits. What have you learnt about the different structures? Hint: You can use the Summary Reports option from the left menu to get comparative data on the structures found.
2. A review of protein-ligand interactions for one structure
Select 1HSG which is one of the entries by typing it in the text box at the top of the PDB home page. This will display a Structure Summary page. Read the abstract under Primary Citation and understand the mode of action of the drug, including the specific interactions between drug and protein that are important.
Select Protein Workshop under the display options and explore the general features of the molecule. Note the homodimeric nature of the molecule and how the drug is bound in the cavity normally occupied by the peptide being cleaved. Close Protein Workshop.
Select Drug Similarity [View] from the section labeled Chemical Component for the entry 1HSG Use the Marvin view option. Notice the chemical similarity to Nelfinavir and Seqinavir – other drugs used as part of a protease cocktail treatment. Try superimposing their 2D structures. Close this window.
From the Structure Summary page for 1HSG Focus on the section labeled Chemical Component select Ligand Interaction [View] as a way to study the details of the protein-ligand interactions. What are the predominant interactions hydrophilic or hydrophobic? What protein residues form the stringest hydrogen biond interactions between protein and drug?
3. Kinetics, chemical properties, toxicity etc
Go to PubChem site which documents a large number of compounds with bioactivity. Search for the term Indinavir. This provides basic physicochemical information as well as an entry point to more detailed literature. What can you discover about the toxicology of the drug?
On your own repeat steps 1-3.