The ultimate goal of many projects at HWI is to develop potential drug molecules that block or otherwise modulate the activity of proteins that have been shown to be relevant in human diseases. For example, a protein may be over active in cancer cells or may induce inflammation. Alternately, a bacterial or viral protein may be essential for  establishing an infection. In either case, characterizing known inhibitors or identifying new molecules that block or inhibit protein activity could lead to the discovery of new drugs.

X-ray crystallography allows the determination of the three-dimensional structures of protein molecules. Structure-based drug design (SBDD) uses this information to find out how small molecules (ligands) interact with a protein’s surface.  With these techniques, structural biologists can understand the features of known drugs that bind to certain proteins, and they can design new molecules that fit the ligand-binding site of a protein in competition with the natural ligand. A helpful analogy is to think of using the inner shape of a lock to build a key that selectively fits just that lock. By design and optimization, an inhibitor molecule can be made to complement important cavities of a protein in terms of its shape and chemical properties.

Many proteins are catalysts (enzymes) that facilitate biochemical reactions.  The region of a protein molecule where a reaction occurs is termed the active site. Understanding the structure of the active site may identify lead compounds for designing better drugs. If a protein functions by breaking a molecule into two smaller parts, an analog that contains an unbreakable chemical bond may be an excellent inhibitor that binds tightly to the active site but fails to react.

In contrast to this rational approach to drug design, another strategy uses high-throughput technologies to identify chemicals that can block a reaction. Biochemical assays are developed that mimic a protein's natural reaction, and libraries of chemicals are tested for the ability to inhibit this reaction. Through this method, molecules are often identified that bind to the active site of an enzyme in an unpredictable way. X-ray crystallography can then be used to determine how the molecule binds to the protein and may suggest changes to the structure of the lead compound that could improve binding. The technology now exists to test hundreds of thousands of compounds in these inhibition assays.

A final approach to drug design is to conduct automated, computer-based (virtual) screening of libraries containing millions of known compounds by docking or fitting them, one at a time, at a ligand-binding site and calculating a score for the degree of binding. Further optimization is carried out to obtain as snug a fit as possible. The compounds with the highest scores can then be assayed for inhibitory activity. Ultimately, their effectiveness in animals, toxicity tests, and other trials can proceed for promising drug candidates.

There are several success stories of SBDD to date, none perhaps more dramatic than the discovery (at Merck & Co.) of HIV protease inhibitors for the treatment of AIDS. Other examples are given at: www.nigms.nih.gov/Publications/structure_drugs.htm. At HWI, scientists are using computational and experimental techniques to develop new protein inhibitors. The figure shows the molecular structure of an inhibitor against a bacterial protein that was identified by high-throughput biochemical screening.

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