GPCR Complex Drug Discovery Services

Traditionally, the primary focus of drug development has been on directly targeting the receptor protein in order to either promote or block receptor activation. However, as many receptor proteins are found in complexes with receptor-associated proteins, this opens up new possibilities for drug discovery. Targeting and regulating certain signaling pathways in ways that are not easily accomplished by conventionally targeting receptor proteins alone is made possible by pharmacological modification of receptor complexes. Creative Biolabs offers GPCR complex drug discovery services. The services have the potential to improve therapeutic efficacy by facilitating more precise control of disease pathways and minimizing side effects.

Composition of GPCR Complex

GPCRs depend on a cytosolic G protein to function, and post-translational changes like as palmitoylation and phosphorylation significantly affect receptor availability and signaling. A core receptor protein or an assembly of receptor subunit proteins that interact with one or more receptor-associated proteins make up a receptor complex. Proteins known as receptor-associated proteins bind directly to the receptor protein, frequently having a significant impact on the composition, capabilities, and/or arrangement of the receptor complex. Thus, phenotypic drug discovery and various observations lead to the realization that certain receptors exist as receptor complexes. These days, more methodical techniques are employed to find novel receptor complexes, such as proteomic and genomic methods.

Fig.1. Structure and function of GPCR complexes.¹

Strategies for Targeting GPCR Complexes

• Targeted searches for small-molecule modulators of these complexes have made use of high-throughput screening (HTS). The absence of structural data on receptor complexes hampered both rational and structure-based medication design. The understanding of protein complex architecture has improved recently, especially with cryo-EM. This has made it possible to identify allosteric binding sites of GPCR monomers as well as homodimers and heterodimers and to develop small molecules that modulate receptor complexes specific to specific subtypes.
• PPIs can also be physiologically tuned to target receptor complexes made up of core receptor proteins and receptor-associated proteins. Targeting PPIs presents a number of well-known difficulties, one of which is developing methods that can bind to big, flat surfaces while retaining their drug-like characteristics. Compounds can, however, influence PPIs in a variety of ways, including binding to a single PPI partner, blocking PPI formation, or altering a PPI's structure through allosteric modulation.

Rethinking screening techniques is necessary when targeting receptor complexes, particularly when investigating heterologously produced receptors that generally lack essential receptor-associated proteins. In light of this, it's critical to identify every protein present in natural receptors. The availability of high-resolution receptor complex structures has made rational and fragment-based drug design possible, allowing for the development of leads for targets that were previously thought to be "undruggable." Creative Biolabs offers GPCR complex drug discovery services, which have the potential to yield novel treatment candidates for a variety of illnesses. Please contact us for more information.

Reference

1. Rosenbaum, Mette Ishøy, et al. "Targeting receptor complexes: a new dimension in drug discovery." Nature Reviews Drug Discovery 19.12 (2020): 884-901.