Accelerating Discovery Success with Structure-Guided Drug Design

The first challenge in drug discovery is selecting a biological target and validating a “druggable” binding site. The key to this is identifying several potent compounds that can be used in more advanced validating assays. To achieve this go/no-go point, suitable chemical starting points need to be found and then, compounds optimized for binding. We have found that protein X-ray crystallography is essential to accelerate the design process by providing a level of structural detail that is unmatched using only computational methods.

Artemis was an unproven target to block DNA-repair in oncology. Progress was slow due to difficulties in protein production, lead chemical matter and lack of experimental protein structures. Curia’s team designed a new protein construct that provided the first crystal structure of Artemis. A unique screening library produced novel hits to an allosteric binding site. The structural biology team co-crystallized several new series in Artemis and ultimately, more than 80 co-crystal structures were provided.

Using collaborative efforts of medicinal and computational chemistry, a structure-driven SAR development provided a 450 fold improvement in IC50’s to this novel binding site. Without these structures, key induced-fit effects could not have been predicted.

Key Learning Objectives:

• Accelerating the design of low nanomolar compounds is essential in target validation.
• The structure-driven SAR process requires excellent structural biology, medicinal and computational integration.

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