Systematic exploitation of multiple receptor conformations for virtual ligand screening

Area of Science:

• Computational chemistry
• Drug discovery
• Structural biology

Background:

• Virtual ligand screening (VLS) is crucial for identifying drug candidates.
• Incorporating receptor flexibility enhances VLS performance.
• Protein plasticity can be represented by multiple crystallographic conformations.

Purpose of the Study:

• To systematically assess the utility of multiple receptor conformations in VLS protocols.
• To evaluate the impact of ensemble receptor-based screening on discriminating binders from non-binders.
• To determine if ensemble methods can improve the enrichment and diversity of active compounds.

Main Methods:

• Systematic analysis of 36 pharmaceutical targets.
• Application of ensemble receptor-based VLS protocols.
• Comparison with single rigid receptor screening methods.
• Utilized actual molecules with reported activity against targets.

Main Results:

• Ensemble receptor-based protocols show superior discrimination between active and inactive molecules compared to single rigid receptor approaches.
• The ensemble method effectively enriches a higher number of active compounds.
• The protocol also enhances the chemical diversity of identified active compounds.
• Identified strategies for selecting optimal receptor conformation subsets for real-world screening.

Conclusions:

• Employing multiple crystallographic receptor conformations in VLS significantly boosts the accuracy and efficiency of drug candidate identification.
• Ensemble receptor-based screening is a powerful strategy for enriching diverse and active compounds in drug discovery pipelines.
• This approach offers a more robust alternative to traditional rigid receptor screening, paving the way for improved hit identification.