A Strategy Combining Differential Low-Throughput Screening and Virtual Screening (DLS-VS) Accelerating the Discovery...

Area of Science:

• Pharmacology
• Computational Chemistry
• Drug Discovery

Background:

• Orphan G protein-coupled receptors (GPCRs) present significant challenges for modulator identification due to a lack of known ligands.
• Existing screening methods can be resource-intensive, requiring extensive experimental testing.
• Developing integrated strategies is crucial for efficient drug discovery targeting orphan GPCRs.

Purpose of the Study:

• To introduce and validate the DLS-VS strategy, an integrated method for identifying chemical modulators of orphan GPCRs.
• To demonstrate the efficacy of DLS-VS in minimizing compound testing while maximizing hit identification.
• To apply the DLS-VS strategy to the orphan receptor GPR34 and identify novel modulators.

Main Methods:

• The DLS-VS strategy integrates differential low-throughput screening (DLS) with virtual screening (VS).
• DLS is used first to identify receptor-specific modulators from a small, diverse compound library.
• Homology modeling, iterative refinement, and VS are employed to build and optimize an active receptor model for large-scale virtual screening.

Main Results:

• The DLS-VS strategy was applied to the orphan receptor GPR34, screening 20,000 compounds experimentally and 1,250,000 compounds virtually.
• The screening successfully identified one agonist and eight inverse agonists for GPR34.
• The identified modulators exhibited significant chemical diversity, highlighting the strategy's ability to uncover novel chemical scaffolds.

Conclusions:

• The DLS-VS strategy provides an efficient and effective integrated approach for identifying chemical modulators of orphan GPCRs.
• This method significantly reduces the number of compounds requiring experimental validation.
• The DLS-VS strategy is broadly applicable to other GPCR targets in drug discovery programs.