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Structure-guided Drug Design

Diagram showing how structure-based drug design affects enzyme function

Potential Benefits

Greater Specificity

  • Iterative design process increases selectivity

Lower Costs

  • Efficient, rapid drug development

Fighting the disease at the active site

In structure-guided 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-guided 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.

BioCryst's structure-guided drug design involves the integrated application of traditional biology and medicinal chemistry along with an array of advanced technologies, including x-ray crystallography, computer modeling of molecular structures, virtual screening, and protein biophysical chemistry to focus on the three-dimensional structure of the active site of the target enzyme.

By identifying the target protein in advance, and by determining molecular structure of the protein, our scientists design a more optimal drug to interact with the protein. BioCryst's scientists design and synthesize drug candidates atom by atom, to fit the active site on the protein, thereby suppressing its biological activity. The initial targets for structure-guided 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-guided 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.

Refining 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. This data, in turn, suggests 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 an iterative 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-guided drug design.

Rapid iterations based on data and evaluation

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

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 optimize 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 shows sub-optimal efficacy in these models, researchers try to understand the reasons (e.g., adverse metabolism, plasma binding, distribution, etc.) and, structure-based drug design provides opportunities to improve the physic-chemical properties of the compound. The optimized compound is then ready for conventional drug development (e.g., studies in safety assessment, formulation, clinical trials, etc.).


Diagram showing how structure-based drug design affects enzyme function

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?

Highly purified proteins can be coaxed to form crystals by slow precipitation from an aqueous solution under appropriate conditions. As the protein molecules are forced out from the solution, they align themselves into a repeating pattern forming small crystals. These protein crystals are the starting point for protein structured determination.

What are the main steps of structure-guided 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 an iterative process.