Fragment Screening and Structure-Guided Development of Heparanase Inhibitors Reveal Orthosteric and Allosteric...

Area of Science:

• Biochemistry
• Enzymology
• Drug Discovery

Background:

• Heparanase is a key enzyme in extracellular matrix degradation, and its overexpression is implicated in various human diseases.
• Existing heparanase inhibitors, primarily substrate mimetics, have not succeeded in clinical trials, necessitating novel inhibitor scaffolds.

Purpose of the Study:

• To explore novel chemical space for heparanase inhibitors using fragment-based drug design.
• To identify and develop small molecule inhibitors targeting heparanase activity.

Main Methods:

• Employed fragment-based drug design combined with crystallographic and computational approaches.
• Screened 31 fragments for heparanase binding, followed by fragment growing to enhance potency.

Main Results:

• Identified 31 fragments that bind to heparanase.
• Five fragments demonstrated heparanase inhibition in the micromolar range.
• Fragment growing led to a compound with a 7-fold increase in potency.

Conclusions:

• The fragment screen revealed untapped chemical space for heparanase inhibitor development.
• This study provides a foundation for creating potent drug leads for heparanase-related diseases.
• The identified compounds hold potential for transforming the treatment of heparanase-associated pathologies.