DARC: Mapping Surface Topography by Ray-Casting for Effective Virtual Screening at Protein Interaction Sites

Area of Science:

• Biochemistry
• Drug Discovery
• Computational Chemistry

Background:

• Protein-protein interactions (PPIs) are crucial in cellular processes but challenging drug targets.
• Traditional drug discovery methods and virtual screening tools struggle with shallow PPI sites.
• Novel computational strategies are needed to identify inhibitors for PPIs.

Purpose of the Study:

• To introduce a new docking strategy, DARC (Docking Approach using Ray-Casting), tailored for PPI sites.
• To evaluate DARC's efficacy in identifying novel small-molecule inhibitors against the Mcl-1 protein interaction site.
• To demonstrate the potential of DARC in drug discovery for challenging PPI targets.

Main Methods:

• Developed DARC, a docking approach that matches surface topography from protein and ligand perspectives.
• Applied DARC for virtual screening against the human antiapoptotic protein Mcl-1.
• Validated top-scoring compounds using biochemical assays to determine inhibition (Ki values).

Main Results:

• DARC successfully identified novel inhibitors of Mcl-1.
• Four of the top 21 screened compounds exhibited clear inhibition in biochemical assays.
• Inhibitor Ki values ranged from 1.2 to 21 μM with good ligand efficiency.
• Identified compounds were structurally distinct from Mcl-1's natural ligand and known inhibitors.

Conclusions:

• DARC is a valuable computational tool for identifying novel inhibitors of protein-protein interactions.
• The DARC strategy demonstrates utility in discovering unique small molecules against challenging drug targets like Mcl-1.
• This approach expands the possibilities for therapeutic intervention in diseases involving PPIs.