Allosteric GPCR Library

Although G-protein-coupled receptors (GPCRs) have emerged as one of the most promising targets for marketed drugs. In recent years, scientists have focused on the development of new ligands for the GPCR. Allosteric modulators bind to GPCRs at sites that are topographically distinct from the orthosteric site, leading to a change in receptor conformation. These ligands can modulate receptor function by acting at allosteric site, which strongly affects the signaling pathway. Thus, the properties of GPCR interactions, both relative to the orthosteric ligand and to the cellular host environment, can be modified in either a positive or negative direction. Receptors occupied by an allosteric ligand can be considered as ‘novel’ receptor types with unique behavior.

BOC Sciences has abilities in designing and synthesizing allosteric GPCR libraries using both ligand- and structure-based methods.

Advantages of Allosteric GPCR

• Greater subtype selectivity
• Higher potential for oral bioavailability
• Novel therapeutic modalities
• Novel therapeutic agents for the treatment of a wide range of psychiatric and neurological human disorders

Figure 1. The allosteric regulation of GPCR by G protein. (Minh Duc, Nguyen.; et al. 2017)

Library Design

CD BioScience has applied both a ligand- and structure-based strategy to design our allosteric GPCR libraries:

Ligand-based approach

1. Firstly, we search for a reference set of known ligands with high activity values using a 3D pharmacophore. And the main focus of this step is on allosteric modulators of class B GPCRs that have been validated
2. Then, two pharmacophore models are created with the reference compound set and validated using training sets of active and non-active ligands
3. Finally, more than 6,200 small molecules will be selected into Pharmacophore-based allosteric GPCR subset based on CD BioScience compound library

Structure-based approach

1. We mainly apply the structure-based method to human Glucagon receptor (GCGR) and human Corticotropin-releasing factor 1 receptor (CRF1R)
2. The corresponding protein structures recorded in the PDB entries are then optimized and used for the docking calculations by employing a Glide docking
3. Compounds with at least 50% score-based efficacy as compared to the co-crystallized ligands are selected as hits and included in the following target set:
• h-GCGR group: 200 compounds
• h-CRF1R group: 7,200 compounds

Figure 2. The allosteric regulation of G protein by GPCR (A) Connections between GPCR-G protein interfaces and the nucleotide-binding. (Minh Duc, Nguyen.; et al. 2017)

Allosteric GPCR Library Characteristics

• Favorable physicochemical parameters and solubility requirements
• No PAINS or toxic substances/unwanted functions: filtered by strict ‘Ro5-like’ physicochemical and most stringent in-house structural filters
• Bioactivity and safety confirmed by preclinical studies and clinical trials
• Structural diversity, medicinal activity, and cellular penetration
• Structural document, IC₅₀, and other chemical and biological data are provided
• All compounds are continually updated
• Compound cherry-picking service is provided

What We Deliver

• Delivered within 2 weeks in any customer-preferred format
• Powders, dry films or DMSO solutions formatted in vials, 96 or 384-well plates
• All compounds have a minimum purity of 90% assessed by ¹H NMR and HPLC
• Analytical data is provided

BOC Sciences provides professional, rapid and high-quality services of Allosteric GPCR Library design at competitive prices for global customers. Personalized and customized services of Allosteric GPCR Library design can satisfy any innovative scientific study demands. Our clients have direct access to our staff and prompt feedback to their inquiries. If you are interested in our services, please contact us immediately!