Information-driven drug design for G protein-coupled receptors (GPCRs)

Traditional G protein-coupled receptor (GPCR) drug discovery uses high throughput screening and cell based assays as the primary tools towards the discovery of active compounds at the receptor. Given the difficulty in stabilizing membrane proteins outside their natural environment, the opportunity to work directly with pure and stable receptor protein was previously not an option, particularly for metastable human GPCRs. This hurdle and other technological challenges limited the industry’s ability to obtain high resolution crystal structures. Using multiple breakthrough technologies, Receptos employs a unique and powerful approach to advance the field and create best- and first-in-class GPCR specific compounds. Receptos utilizes a comprehensive information-driven approach to GPCR drug discovery that combines traditional screening information with biophysical ligand screening using pure and stable receptor protein, chemistry structure-activity relationships, novel biological insight into allosteric binding sites, site specific mutagenesis to probe residue-ligand interactions, GPCR crystal structure, and co-crystal structure iterations.

Receptos is able to accomplish this task using a series of pioneering technologies developed at The Scripps Research Institute at multiple stages in the structural biology process including: design and generation of stable receptor protein, novel chemical tool development insight, high throughput analytical examination of receptor and receptor-ligand interactions, biophysical ligand screening, crystallization in a stabilized membrane environment using nanomimetic membrane materials, novel crystal imaging and detection, and micro-crystal data collection. Receptos studies only human proteins, and mutagenesis in the ligand binding site is avoided to create the optimal template for human GPCR drug discovery.

Unlike with traditional structure-based drug discovery where each step in the drug discovery process can be independently conducted, GPCR structure determination requires very tight integration of the related drug discovery disciplines. This is particularly important between chemistry and structural biology where tool compounds must be synthesized to discovery and stabilize different receptor conformational states. The Receptos information-driven GPCR drug discovery approach creates the most complete data package possible for a drug candidate prior to the decision to invest in costly clinical trials.

Through tight and efficient integration of chemistry, biology, and structural biology, Receptos is able to use this information to discover and thoroughly examine new binding sites and design novel small molecules leading to exciting advances in GPCR drug discovery.