Struct2Query: Structure-Guided Virtual Screening via Composite-Molecule ROCS Queries Derived from Protein Pocket...

Area of Science:

• Computational chemistry
• Drug discovery
• Structural biology

Background:

• Ligand-based virtual screening (e.g., ROCS) is fast but requires known actives, limiting scope.
• Structure-based docking is less constrained but computationally expensive for large libraries.
• Bridging these methods is crucial for efficient, broad-spectrum virtual screening.

Purpose of the Study:

• To introduce Struct2Query, a novel workflow for structure-informed virtual screening.
• To enable rapid exploration of chemical libraries using protein pocket information.
• To overcome limitations of existing ligand-based and structure-based screening methods.

Main Methods:

• Struct2Query converts protein pockets into composite-molecule ROCS queries.
• Utilizes OpenEye SiteHopper to find analogous protein pockets in a large crystallographic database.
• Generates ensemble binding hypotheses by transplanting ligands and retaining all features for ROCS queries.

Main Results:

• Struct2Query matches or exceeds performance of Glide and HYBRID docking on DEKOIS 2.0 and DUDE-Z datasets.
• Achieves throughput compatible with GPU-accelerated FastROCS, maintaining ligand-centric speed.
• Demonstrates improved scaffold diversity and chemotype coverage compared to single-ligand ROCS screening.

Conclusions:

• Struct2Query effectively bridges structure-based and ligand-based virtual screening.
• Offers a scalable and efficient method for structure-informed drug discovery.
• Enhances hit list diversity, enabling broader exploration of chemical space.