Structural Biology and Structure Based Drug Design

StaR^® (Stabilized Receptor) technology

Orexia Therapeutics collaborates with Sosei Heptares in designing new therapeutic agents with optimized pharmacology using StaR^® (Stabilized Receptor) technology, which allows us to stabilize a GPCR protein by engineering a small number of single point mutations outside of the ligand-binding site such that they retain their organized structure even after they are removed from the cell membrane.

The resulting stabilized proteins (StaR^® proteins) are much more robust than the corresponding “wild-type,” or unmutated, proteins.

These StaR^® proteins are more readily purified and subjected to a variety of hit discovery and biophysical approaches.

StaR^® proteins enable crystallization for detailed X-ray or Cryo-EM structure determination, which facilitates the design of innovative medicines with better safety and efficacy profiles and lower preclinical and clinical attrition rates compared to wild-type proteins.

Orexia Therapeutics has an exclusive licence to Sosei Heptares’ StaR^® technology for OX1R and OX2R drug discovery and development allowing us to leverage unique Structure Based Drug Design (SBDD) capabilities at Sosei Heptares.

Schrödinger’s FEP+ is a method for predicting key chemical properties including potency, selectivity and solubility at an accuracy approaching experimental methods. The technology enables the exploration of large chemical space quickly and efficiently and also unleashes creativity of discovery teams by giving them the ability to pursue novel design ideas and challenging chemical series with a high degree of confidence.

Drug Discovery Hit-ID

DNA-encoded libraries (DEX™)

We have partnered with X-Chem, the leader in small molecule drug discovery, to access their DNA-encoded library technology platform.

X-Chem’s screening platform is based on a >200 billion member small molecule library, generated by iterative combinatorial synthesis of small molecules tethered to DNA tags that record the synthetic history of the small molecule. Due to the size and diversity of their library, X-Chem can discover multiple series of novel, potent and selective lead compounds at an unprecedented rate of success against a wide range of targets, including some that previously failed using conventional screening methods.

The collaboration is a result of X-Chem screening its drug-like DEX™ against a stabilized OX2R receptor generated through Orexia Therapeutics’ exclusive access to Sosei Heptares’ OX2R StaR protein. X-Chem subsequently used DEX™ screening data and its advanced informatics platform to provide Orexia with small molecule leads for further optimization.

Intranasal Drug Delivery

Bi-Directional™ Exhalation Delivery Systems (EDS)

Drug delivery is a particularly difficult challenge for CNS-targeted drugs, and compound properties compatible with oral dosing can limit the diversity of compounds that can be considered as therapeutic agents. In order to expand the diversity of orexin agonist clinical candidates, Orexia Therapeutics has exclusively licensed the Optinose technology for intranasal drug delivery of orexin agonists and/or orexin positive modulators.

Despite the easy access to nasal cavities, the complex geometry of the nose makes reliable and efficient delivery of drugs to mucosal surfaces high and deep in the nose challenging.

The Optinose EDS technology is designed to deliver drugs in the upper nasal passages with potential improvement compared to traditional spray pumps and pressurized metered-dose aerosols.

Find out more and watch a video about the Anatomy of the Nasal Passages from Optinose.