Structure-based drug design

Potential Benefits

Greater Specificity
- Iterative design process increases selectivity
Lower Costs
- Efficient, rapid drug development

Fight the disease at the active site

In structure-based drug design, scientists use detailed knowledge of the active sites of protein targets associated with particular diseases to design synthetic compounds that fight the disease. The active site of an enzyme is the area into which a chemical or biological molecule fits to initiate a biochemical reaction. Structure-based drug design aims to create a molecule that will bind to the active site of a targeted enzyme, thereby preventing the normal chemical reaction and ultimately halting the progression of the disease.

The Company's structure-based drug design involves the integrated application of traditional biology and medicinal chemistry along with an array of advanced technologies, including X-ray crystallography, combinatorial chemistry, computer modeling of molecular structures and protein biophysical chemistry, to focus on the three-dimensional molecular structure and active site characterization of the proteins that control cellular biology.

Improvement over traditional techniques

BioCryst believes that structure-based drug design is an improvement over traditional drug screening techniques. By identifying the target protein in advance, and by discovering the chemical and molecular structure of the protein, our scientists believe it is possible to design a more optimal drug to interact with the protein. BioCryst's scientists design and synthesize drug candidates atom by atom, to fit an active site on the protein, thereby inhibiting its biological activity. The initial targets for structure-based drug design are selected based on their involvement in the biological pathways integral to the course of a disease. This approach is much more target-specific than the random screening methods that have dominated pharmaceutical development in the past. Recent successes from structure-based drug design include several of the HIV protease inhibitors that are now widely used to treat HIV patients.

Determining the molecular structure

Once a target is selected, researchers use X-ray crystallography to determine the precise three-dimensional molecular structure of the proteins. This structure serves as a blueprint for the drug design of a lead compound. The compounds are modeled for their fit in the active site of the target, considering both steric aspects (i.e., geometric shape) and functional group interactions, such as hydrogen bonding and hydrophobic interactions.

Refine lead compound

Following the initial design phase, scientists synthesize the lead compound and measure quantitatively its ability to interact with the target protein; they also use X-ray crystallography to analyze the compound-target complex. This analysis reveals important, empirical information on how the compound actually binds to the target and the nature and extent of changes induced in the target by the binding. These data, in turn, suggest ways to refine the lead compound to improve its binding to the target protein.

The refined lead compound is then synthesized and complexed with the target, and further refined in a reiterative process. If lead compounds are available from other studies, such as screening of combinatorial libraries, these compounds may serve as starting points for this optimization cycle using structure-based drug design.

Evaluate the compound in a physiological environment

Once a sufficiently potent compound has been designed and optimized, its activity is evaluated in a biological system to establish the compound's ability to function in a physiological environment. If the compound fails at any stage of the biological evaluation, the design team reviews the structural model and uses crystallography to adjust structural features of the compound to overcome the difficulty. This process continues until a designed compound exhibits the desired properties.

The compound is then evaluated in an experimental disease model. If the compound fails, researchers determine the reasons for failure (e.g., adverse metabolism, plasma binding, distribution, etc.) and, again, design new modified compounds to overcome the deficiencies without interfering with the compound's ability to interact with the active site of the target protein. The experimental drug is then ready for conventional drug development (e.g., studies in safety assessment, formulation, clinical trials, etc.).

Rapid iterations based on data and evaluation

This reiterative analysis and compound modification are possible because of the structural data obtained by X-ray crystallography at each stage. This capability renders structure-based drug design a powerful tool for rapid and efficient development of drugs that are highly specific for particular protein target sites.

Crystallography

What is crystallography?

Crystallography, or the study of crystals, is the scientific discipline that is at the center of structure-based drug design. Crystals are solid substances with symmetrically arranged molecules. Obtaining large, well-ordered crystals is essential for a crystallographer to be able to analyze the three-dimensional molecular structure and active site of the proteins that control cellular biology.

How are crystals grown?

Crystals are created or grown by first collecting and purifying a small quantity of the target enzyme and then by setting up a system to evaporate most or all of the water molecules that are mixed in with the enzyme. By removing the water, the enzyme is left in a hardened or crystallized form.

What are the main steps of structure-based drug design that involve crystallography?

BioCryst's scientists use X-ray crystallography throughout the process of designing and optimizing potential drugs. First, they use crystallography to determine the structure of their target proteins. This structure is used to design potential compounds that will fit the active site of the target.

Scientists then use crystallography to study how compounds bind with the active site of the target protein. Using information gained through crystallography, researchers refine the compounds to improve their performance. The redesigned lead compound is then synthesized and further refined and analyzed in a reiterative process.