Virtual Screening Strategy to Identify Retinoic Acid-Related Orphan Receptor γt Modulators.

Area of Science:

• Medicinal Chemistry
• Computational Drug Discovery
• Pharmacology

Background:

• Molecular docking is crucial for virtual screening (VS) in drug discovery but often struggles to differentiate active ligands from inactive molecules.
• Retinoic acid receptor-related orphan receptor gamma t (RORγt) is a significant therapeutic target for inflammatory conditions like psoriasis and multiple sclerosis.

Purpose of the Study:

• To develop and validate a novel, shape-focused pharmacophore VS protocol for enhanced hit discovery.
• To identify novel small-molecule inhibitors for RORγt using the developed VS strategy.

Main Methods:

• Flexible docking of a commercial molecular database against the RORγt target.
• Rescoring docking poses using negative image-based (NIB) models that represent the binding cavity's shape and electrostatic potential.
• Pharmacophore point-based filtering and free energy binding affinity evaluation to prioritize hits.

Main Results:

• The developed VS protocol identified 28 compounds for in vitro testing.
• Eight compounds demonstrated low μM inhibitory activity against RORγt.
• The protocol achieved an effective hit rate of approximately 29%.

Conclusions:

• The novel docking and shape-focused pharmacophore VS protocol significantly improves hit discovery efficiency for challenging targets like RORγt.
• This approach provides a robust method for identifying potent inhibitors for therapeutic development in inflammatory diseases.