Compound Prioritization in Single-Concentration Screening Data Using Ligand Efficiency Indexes

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• High-throughput screening (HTS) requires efficient compound triage.
• Ligand efficiency indexes are established for dose-response phases but less studied in single-concentration screening.
• Multiobjective optimization is crucial for selecting potent and physicochemically suitable hits.

Purpose of the Study:

• Investigate the utility of ligand efficiency indexes for prioritizing compounds in single-concentration HTS.
• Provide formulas for deriving these indexes from single-concentration data.
• Evaluate the statistical association between single-concentration and dose-response ligand efficiency indexes.

Main Methods:

• Derived formulas for single-concentration ligand efficiency indexes.
• Evaluated statistical association using historical HTS data across diverse target classes and technologies.
• Performed permutation tests to assess contributions of physicochemical properties and biological activity.
• Analyzed cost/benefit of different index thresholds for compound rescue.

Main Results:

• Achieved Pearson's correlation coefficients (r) above 0.9 for compounds with dose-response curves.
• Obtained areas under the curve (AUC) of receiver operating characteristic (ROC) curves above 0.85.
• Demonstrated significant statistical association, confirming contributions from both physicochemical and biological factors.
• Provided cost/benefit curves to guide threshold selection for efficient compound rescue.

Conclusions:

• Single-concentration ligand efficiency indexes are valuable for hit prioritization in HTS.
• Proposed approximate thresholds to maximize rescue of efficient compounds while minimizing costs.
• Demonstrated a practical implementation using compound clustering, achieving higher rescue rates at lower costs compared to response-driven selection.