Today's workshop is focused on the use of computers in modern drug design. The presentation is designed to allow you to interactively participate and try some of the activities performed by researchers who use computers to discover and optimize medicinally useful materials.

• What is a drug?
• A brief history of drug discovery and development.
• The current roles of the computer in drug design.
• Hands-on exercises of computer use in drug design.

• A drug is a substance used in the treatment or prevention of disease.
• Drugs usually work in one of three ways:
  • By interfering with the biological function of viruses, bacteria or parasites.
    • Antibiotics all fall in this category
    • HIV drugs currently available interrupt the function of either the reverse transcriptase or protease enzymes in the Human Immonodeficiency Virus. These enzymes are critical for viral functions.
  • By blocking interaction of viruses, bacteria or parasites with our systems.
  • By interfering with or enhancing our own biological function(s).
    • Immunizations enhance our immune response to disease.
    • Insulin helps regulate sugar levels in the bloodstream for diabetic patients
    • Cancer medications try to stop abnormal cell growth

• Storing and retrieving information
  • Structures determined experimentally by X-Ray crystallography for biological targets (enzymes) and drug molecules
  • Molecules and activities testing the affect of small structural changes on biological activity
  • Information about toxicity and its relationship to structure
• Visualizing molecules
  • Similarities/differences between drugs acting in the same way
  • Interaction between drugs and receptors
• Calculations
  • Interaction strengths
  • Motion (dynamics)

Introduction: The Human Immunodeficiency Virus

The Human Immunodeficiency Virus (HIV) is the biological agent responsible for Acquired Immunodeficiency Syndrome (AIDS). HIV requires the activity of three large molecules (enzymes) in order to function properly. Disrupting any of these three enzymes is a potentially useful strategy for developing drugs to treat AIDS patients. We will be looking at one of these enzymes, HIV-protease. Interference with the activity of this enzyme (called inhibition) is a very active area of current research.

Storing and retrieving information

Your assignment is to use the Protein Databank to find some crystal structures of the enzyme HIV-protease (Human Immunodeficiency Virus-1 Protease). Click on the link above and then click on "Searching and Browsing the PDB". Then click on the new "3DB Browser" link.

Visualizing molecules

• Similarities/differences between drugs acting in the same way
  • Four HIV-Protease Ligands - Examine the four HIV-protease ligands. Try to orient them all on screen so that they present approximately the same shape and have similar functionality in similar places. (Red atoms are oxygen, blue are nitrogen, white are hydrogen and grey are carbon).
• Interaction between drugs and receptors
  • HIV-Protease Ligands Bound to the Enzyme - Examine the structures of the enzyme-ligand complexes. Try to find the ligands within the enzymes before using the buttons that will highlight the ligands.

Calculations

• Interaction strengths
• Motion (dynamics)

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Abby Parrill
Department of Chemistry
The College of Natural Science
Michigan State University

These pages may be downloaded and linked from other pages freely for academic and educational purposes. Questions, problems, and errors should be sent to parrill@argus.cem.msu.edu.