Capabilities - Structure to Lead

Sareum uses a highly focused method of lead identification which uses template-based screening, structure based design and lead elaboration using automated medicinal chemistry.

Structure to lead

Template Screening

At Sareum we use our own fragment/template-based screening method to accelerate the generation of novel lead series in drug discovery programmes by identifying many different hit molecule chemotypes. Using this approach, crystal structures of target proteins are solved with Sareum-derived drug templates which then allows rapid chemical optimisation using Sareum's automated chemistry platform.

The initial template molecules are carefully selected by our computational and medicinal chemists to contain key pharmacophores and functional groups with beneficial physicochemical properties. Biochemically active molecules can then be elaborated or combined with one another to provide high affinity leads amenable to rapid optimisation on our highly automated chemistry platform. Compounds are synthesised, biochemically assayed and further co-crystal complexes prepared, enabling structure-activity relationships (SAR) to be understood. This fast iterative process drives the development of novel, potent and selective drug leads for specific protein targets.

Hit to Lead

Template Hits, active against the chosen target are assessed and prioritised based on their IP position and optimisability profile. Optimisability is a combination of synthetic tractability and potential for making desirable interactions with the protein target, a function of a molecule's shape and the functional groups it bears.

Our medicinal chemists use the co-complex structure of the Template Hit with the protein target to assess the suitability of a molecule for optimisation and then synthetic derivatives of the Template Hit are designed to access additional regions of the protein important for improving potency and selectivity against related proteins.

Hit to lead

The proposed synthetic modifications are explored computationally through the generation of virtual libraries. These virtual libraries are assessed in silico to ensure they have suitable physicochemical properties, and are then virtually screened using docking based on the pose of the initial Template Hit.

Compounds predicted to interact favourably with the protein target are then nominated for synthesis. Optimisation occurs through the preparation of highly focussed libraries of up to 96 compounds - preferably utilising Sareum's high-throughput medicinal chemistry platform. After purification, the molecules are biochemically assayed and protein-ligand structures determined by X-ray crystallography. Through these iterative techniques, our scientists are able to build up an in-depth understanding of the way molecules interact with the protein target, enabling them to rapidly optimise Template Hits into Template Leads.

Elaboration of Leads

Sareum has a highly automated chemistry platform capable of reproducing the majority of reaction conditions encountered in modern chemical synthesis. The platform is modular, and is therefore capable of incorporating new technologies and evolving to suit changing needs. It also requires minimal manual intervention during the reagent / reactant dispensing, reaction and work-up phases of the synthetic scheme, so is suitable for the automated synthesis, analysis and purification of small and mid-sized arrays of compounds, typically on a multi mg scale.

The automated synthesis platform allows the rapid synthesis of lead-like and drug-like molecules using a wide-ranging repertoire of reactions and conditions. Capabilities include:

Solution-phase synthesis
Solid-phase synthesis
Extensive use of supported reagents and scavenging resins
-78°C to +250°C, inert atmosphere, slow addition
Microwave Chemistry
Synthesis from g to mg scale

All products from synthesis and purification are analysed by LC/MS. Purity is measured by UV detector at two wavelengths (215 and 254 nm) and by evaporative light scattering detector. Molecular weight of the (ionised) products are recorded by mass spectrometry running in both positive and negative ionisation mode. Products are ionised using electrospray methodology. Sareum's 400MHz NMR with automated sample handling allows structure confirmation and further verification of purity.