Design of allosteric modulators that change GPCR G protein subtype selectivity

Area of Science:

• Pharmacology and Drug Discovery
• Molecular and Cellular Biology
• Biochemistry

Background:

• G protein-coupled receptors (GPCRs) are a major drug target class, interacting with 16 Gα protein subtypes.
• Biased GPCR ligands offer potential for safer, more effective therapies, but their design is hindered by poor understanding of bias determinants.
• Rational design of G protein-subtype-selective compounds is currently lacking.

Purpose of the Study:

• To investigate how small molecules binding the intracellular GPCR-transducer interface influence G protein coupling.
• To enable rational drug design by understanding subtype-specific mechanisms of G protein bias.
• To develop a strategy for pathway-selective drug discovery across the GPCR superfamily.

Main Methods:

• Utilized the neurotensin receptor 1 (NTSR1), a class A GPCR, as a model system.
• Employed small molecules, including SBI-553, to probe the GPCR-transducer interface.
• Analyzed structural mechanisms of G protein coupling and selectivity using chemical modifications and in vivo studies.

Main Results:

• Demonstrated that small molecules can alter NTSR1 G protein coupling through subtype-specific mechanisms.
• SBI-553 acts as a 'molecular bumper' and 'molecular glue,' promoting selective G protein subtype association via altered binding conformations.
• Minor scaffold modifications yielded allosteric modulators with distinct, probe-independent, and species-conserved G protein selectivity profiles that translated to in vivo activity.

Conclusions:

• G protein selectivity can be precisely tailored by targeting the receptor-transducer interface with small chemical scaffolds.
• The identified pocket for targeting is broadly conserved across GPCRs, suggesting a widely applicable drug discovery strategy.
• This approach offers a pathway to developing safer, more effective, pathway-selective GPCR-targeted medications.