Protein structure similarity as guiding principle for combinatorial library design

Area of Science:

• Structural biology
• Medicinal chemistry
• Drug discovery

Background:

• Proteins are constructed from a limited repertoire of approximately 1000 structural domains.
• Evolutionary relationships within protein domain families indicate shared fold structures.
• Knowledge of common folds can guide the design of small molecule inhibitors and ligands.

Purpose of the Study:

• To explore the utility of common protein fold structures in designing small molecule inhibitors.
• To demonstrate the application of this principle across different protein families and functional classes.

Main Methods:

• Utilizing known protein fold structures as templates for inhibitor design.
• Applying a guiding structure (Bestatin) for developing inhibitors against new targets.
• Employing combinatorial approaches to identify inhibitors for specific enzyme families.

Main Results:

• Successfully synthesized inhibitors for kinases that share common fold structures.
• Developed leukotriene A4 hydrolase inhibitors using an aminopeptidase inhibitor (Bestatin) as a guiding structure.
• Identified inhibitors for sulfotransferases by leveraging structural similarities to nucleotide kinases and using a kinase inhibitor core.

Conclusions:

• Common protein fold structures provide a powerful framework for the rational design of small molecule inhibitors and ligands.
• This approach is applicable to diverse protein targets, including those with different functional roles but shared architectures.
• The strategy facilitates efficient drug discovery by enabling the repurposing of existing knowledge and guiding structures across protein families.