TOKYO & PARIS—Sosei Heptares, an international biopharmaceutical group focused on G protein-coupled receptors (GPCRs), has selected 3decision software from Discngine SAS, a Paris-based software company specializing in developing applications for life-sciences research. The software will be employed specifically for work related to active molecule discovery, to be part of Sosei Heptares’ structural GPCR chemogenomics platform.
The software will enable Tokyo-based Sosei Heptares to combine public and proprietary structural data and derive unique GPCR structural insights from it, according to the companies.
As Chris de Graaf, director and head of computational chemistry at Sosei Heptares, explained, “Collaborating with Discngine and integrating our unique GPCR structural information in 3decision will enable us to reveal unprecedented SBDD [structure-based drug design] opportunities. We expect 3decision to make the combined analysis of experimentally derived structural information and in-silico predictions within our structure-based drug design projects more efficient.”
Peter Schmidtke, 3decision’s product manager at Discngine, added, “Sosei Heptares is continuously sharing new structural insights and unique GPCR X-ray structures with the global community, thereby increasing the overall knowledge of GPCRs. Discngine and Sosei Heptares will work closely together to fine-tune 3decision to leverage mutagenesis-data analytics. This collaboration will add even more value to our software solutions.”
Schmidtke related that 3decision is a structural knowledge management solution that provides structural analysis, disruptive design and modern integration in a standard web browser. It provides access to the entire structural knowledge space—annotated, curated and well displayed—increasing productivity on everyday redundant tasks involving the Protein Data Bank and UniProt. All of this aids in exploiting the full potential of structural data by registering historical data and new structures along with models and validated docking poses, as well as expediting the discovery pipeline and enhancing the efficacy and safety of molecules by using state of the art structural data and advanced structure analysis methodologies without any expert knowledge. The program reportedly helps users to keep R&D agile and sustainable, benefit from collective intelligence, increase productivity, facilitate collaboration, integrate with other applications and secure data.
The 3decision software will help Sosei Heptares scientists to more efficiently derive structural GPCR insights from the structural data at hand, directly benefitting the internal SBDD projects and reinforcing Sosei Heptares’ expertise in GPCR structural cheminformatics. Additionally, 3decision is expected to make it easier for Sosei Heptares to combine its unique structural information with GPCR modelling, cheminformatics capabilities, mutagenesis data and the information provided by its StaR (Stabilized Receptor) technology. For example, 3decision will allow Sosei Heptares to easily visualize and analyze mutagenesis data in 3D, via a web-accessible front end.
The StaR technology forms the backbone of Sosei Heptares’ integrated SBDD platform, which “unlocks” the potential of GPCRs through an advanced understanding of their structure. The technology can stabilize a GPCR by engineering a small number of single point mutations outside of the ligand-binding site to retain their organized structure even after they are removed from the cell membrane. The resulting stabilized proteins (StaR proteins) are said to be 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.
Patent-protected technologies from Sosei Heptares enable unique structural insights into GPCRs as drug targets. With the ability to design new therapeutic agents with optimized pharmacology using SBDD, the Sosei Heptares approach can deliver drug candidates with improved physicochemical properties, enhanced safety and efficacy profiles and reduced clinical attrition rates. The company’s strategy is to target well-characterized biomolecular pathways with high degrees of validation to ensure a strong likelihood of generating a therapeutic benefit, and to exploit its technology advantage to stabilize GPCRs in desired conformations to enable first-time SBDD insights.
This approach has led to a broad early-stage pipeline, with several novel candidates partnered with leading pharmaceutical companies. The platform's capability enables the engineering of functional, stabilized GPCRs (StaR proteins) in their natural pharmacological conformations (agonist or antagonist), including orphan receptors; determination of 3D structures of GPCRs and complexes with bound ligands by X-ray crystallography, cryo-EM and biophysical mapping; deployment of advanced fragment-based drug discovery approaches to GPCRs; full integration of GPCR pharmacology and medicinal chemistry; and design of novel agents directed towards high-value yet historically challenging or undruggable GPCR drug targets.