Design of allosteric modulators that change GPCR G protein subtype selectivity

Area of Science:

• Pharmacology
• Molecular Biology
• Drug Discovery

Background:

• G protein-coupled receptors (GPCRs) are major drug targets, interacting with 16 Gα protein subtypes.
• Biased GPCR agonists offer potential for safer, more effective therapies, but their design is challenging.
• Understanding the determinants of G protein bias is crucial for rational drug design.

Purpose of the Study:

• To investigate how small molecules binding the GPCR-transducer interface influence G protein coupling selectivity.
• To develop rationally designed, G protein-subtype-selective compounds for GPCRs.
• To explore the potential of targeting the intracellular interface for pathway-selective drug discovery.

Main Methods:

• Utilized the neurotensin receptor 1 (NTSR1) as a model class A GPCR.
• Employed small molecules, including SBI-553, to modulate GPCR-G protein interactions.
• Performed structural and functional analyses to determine mechanisms of G protein subtype selectivity.

Main Results:

• Identified that small molecules can alter NTSR1 G protein coupling through subtype-specific mechanisms.
• Demonstrated SBI-553 acts as a 'molecular bumper' and 'glue' to promote selective G protein association.
• Showed that minor scaffold modifications yield allosteric modulators with distinct G protein selectivity profiles.
• Confirmed probe-independent and cross-species conserved selectivity translating to in vivo effects.

Conclusions:

• GPCR G protein selectivity can be precisely tailored by targeting the receptor-transducer interface with small molecules.
• This strategy offers a broadly applicable approach for developing pathway-selective drugs across the GPCR superfamily.
• The conserved nature of the binding pocket suggests wide applicability for rational, biased drug design.