University of Alabama at Huntsville
Structural Biology Laboratory
Steps of the Rational Drug Design Process

Updated: March 13th, 2008

Dr. Joe Ng, Assistant Professor of Biology and Biochemistry at UAH explains how  to isolate the target protein you wish to work with. For example, a protein which produces an enzyme associated with the initiation or spread of a particular disease would be a good target protein.
In order to study a particular protein macromolecule, a high quality crystal must be produced.  Mrs. Anna Holmes describes the factors involved in the production of  a good quality protein crystal.  In our experiment, the concentration of the lysozyme protein solution is controlled by the amount of  salt added to the solution as water has a higher affinity for salt than lysozyme protein.
The crystal system and the quality of the protein crystals produced depend on the concentrations of the protein and salt solution and the pH . The slower the rate of crystallization, the higher quality of the crystals produced. Lysozyme protein crystals have been produced in the monoclinic, triclinic, and orthorhombic crystal systems.
The microgravity environment of space currently produces the best quality protein crystals.   The ideal crystal should be able to grow slowly in all directions without interference. Crystals grown on Earth are subject to sedimentation affect, uneven protein solution concentration, and a faster diffusion rate which cause imperfections in the structure of the growing crystal.
A high quality protein crystal is mounted in the xray crystallography machine.  Electrons are fired at the crystal producing a scatter pattern which is unique to the atomic structure of the target protein molecule.
Once a xray diffusion pattern is produced, it must be analyzed to produce the molecular structure of the target protein.  Advanced graphics techniques and computer software are used to analyze the molecular structure of the protein molecule.  Once the 'active site' of the molecule is identified, 'blocker' molecular structures can be designed to stop the enzyme production of the target protein.
This is the Lysozyme protein macromolecule atomic structure.  Notice the 'active site' which is indicated by the red atoms.
Once the atomic structure of the target protein is known and the active site determined, a 'blocker' molecule can be designed to stop the production of the undesired enzyme. This is known as the 'lock and key' principle which is the concept behind rational drug design.  This new technology can also be used in the formulation of advanced food products for long duration space missions as well as other applications.  

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