Welcome to SET Day 1997

Computers in Drug Design

Dr. Abby Parrill and Charles Ngowe

Today's presentation 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 medically useful materials.

What is a drug?

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 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

A brief history of drug discovery and development

Evidence of the use of medicines and drugs can be found as far back in time as the first Egyption dynasty, 3100 B.C. For the majority of the time drugs have been used, discovering them has been a trial-and-error process. It was not until the 1960's that some understanding began to develop about the quantitative relationship between structure and biological activity. This new understanding that a quantitative relationship existed ushered in the beginnings of computer-aided drug design.

The current roles of the computer in drug design

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
  - Activity: Go to a website maintained by the University of Utah to search for a materials safety data sheet (MSDS). You may search for any chemical you like, but if you can't think of one you might look for common things like ethanol (found in beer and wine), aspirin, acetaminophen (the painkiller found in Tylenol and Excedrin) and ibuprofen (the painkiller found in Motrin). If an MSDS is available, scan through it to find section 5 - health hazard data.
Visualizing molecules
- Similarities/differences between drugs acting in the same way
- Interaction between drugs and receptors
Calculations
- Interaction strengths
- Motion (dynamics)

Hands-on exercises of computer use in drug design

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 the "3DB Browser" link.
Visualizing molecules
Calculations