Ligand retargeting by binding site analogy

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• MutT homolog 1 (MTH1) is a DNA-repair enzyme implicated in various cancers.
• MTH1's active site shares structural similarities with aspartic proteases, suggesting potential for inhibitor repurposing.

Purpose of the Study:

• To investigate the feasibility of repurposing aspartic protease inhibitors for MTH1.
• To identify potent and selective MTH1 inhibitors using a structure-based drug design approach.

Main Methods:

• In silico screening of a library of aspartic protease inhibitors against MTH1.
• Fragment-based drug discovery, including docking, assays, molecular dynamics, and X-ray crystallography.
• Structure-guided optimization and synthesis of lead compounds.

Main Results:

• Identified three initial fragment hits with good ligand efficiency (IC50 <50μM).
• Evaluated seven compounds in vitro, with two showing submicromolar potency for MTH1.
• Developed a lead compound (compound 11) with nanomolar affinity and >2000-fold selectivity over BACE1.

Conclusions:

• Ligand repurposing based on binding site analogy is an efficient strategy for MTH1 inhibitor development.
• The identified lead compound demonstrates significant potential as an anti-cancer therapeutic agent.
• Structure-activity relationship studies and crystallography were crucial for successful hit optimization.