Computational protein design examples

This example is one where the accurate three-dimensional structure of the protein is unknown under these circumstances, it is necessary to create a computer model. The development of inhibitors that are designed to overcome the effects of this mutation could not be based on the accurate structure of a ligand-binding site here, ligand-based design would be appropriate (see Sect. 7.9). 

For example, with the crystal structure of the aspartyl protease from human immundeficiency virus (HIV-1) in 1989 came the opportunity to design molecules to block this important enzyme that acts as a molecular scissors. HIV is the virus responsible for AIDS. Essential to viral replication, the HIV protease cuts long strands composed of many proteins into the functional proteins found in mature virus particles. This proteolysis occurs at the very end of the HIV replication cycle (Figure 7-1). The three-dimensional structural information derived from the x-ray crystal structure, combined with computer modeling techniques, allowed chemists to design potent, selective inhibitors of the protease enzyme (Figure... 

Currently, this is a major application of protein crystallography in most of the major drug companies. One of the best examples of this approach is the design of inhibitors for HIV protease (Dash et al., 2003). In brief, once the 3-D structure of HIV protease was determined, the active site was identified and used to screen small molecule libraries for potential compounds that could bind to HIV protease. These compounds were then tested for their ability to inhibit the protease. Lead compounds were then used to iteratively improve the inhibitors, using crystallographic studies, computational modeling, and biochemical tests. 

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