A shape-based 3-D scaffold hopping method and its application to a bacterial protein-protein interaction

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Drug Discovery

Background:

• The ZipA-FtsZ protein-protein interaction is a potential target for novel antibacterial agents.
• High-throughput screening (HTS) identified initial hits, but these may possess development liabilities.
• Exploring diverse chemical scaffolds is crucial for identifying effective drug leads.

Purpose of the Study:

• To prospectively apply the ROCS (Rapid Overlay of Chemical Structures) program for identifying novel scaffolds targeting the ZipA-FtsZ interaction.
• To evaluate the effectiveness of shape-based similarity searching compared to traditional methods.
• To validate the predicted binding modes of newly identified inhibitors through experimental methods.

Main Methods:

• Utilized the ROCS (Rapid Overlay of Chemical Structures) program for shape-based chemical structure comparison.
• Used the crystallographically determined bioactive conformation of an HTS hit as the reference.
• Synthesized and tested identified novel inhibitors for binding affinity to ZipA.
• Performed X-ray crystallographic analysis to confirm inhibitor binding modes.

Main Results:

• Identified a set of novel, weakly binding small molecule inhibitors.
• The identified scaffolds possess synthetic opportunities for improved biological affinity.
• ROCS-discovered scaffolds were distinct from those found using 2D fingerprint methods.
• X-ray crystallography confirmed the accurate prediction of binding modes by ROCS.

Conclusions:

• The shape-comparison program ROCS is effective for identifying novel scaffolds for antibacterial drug discovery.
• ROCS enables successful chemotype switching or "lead hopping" by finding structurally distinct inhibitors.
• This approach offers a valuable strategy for lead identification, potentially avoiding issues associated with initial HTS leads.