Natural Product Chemistry
One of Selcia Discovery’s differentiated strengths are its credentials in the optimisation and structural simplification of natural products to overcome issues of compound supply, physicochemical properties, and DMPK leading to novel IP and reduced cost of goods. Selcia has a particularly strong track record of delivering clinical candidates from natural product starting points (four candidates during the past three years). Our strategy typically involves two possible approaches.
- Fermentation, isolation and subsequent modification of the natural compound by semi-synthesis to optimise potency, drug properties and leading to novel IP.
- In cases where the fermentation is difficult and/or the natural compound unstable, we have successfully overcome the obstacles by total synthesis. In some cases, this strategy also enabled a reduction in molecular complexity.
Selcia works with a number of strategic partners to outsource strain optimisation and fermentation capabilities with purification and analysis being carried out in-house.
We have strategic alliances to gain access to novel collections of isolated, purified and characterised natural products that can be screened against new targets to provide novel starting points for subsequent optimisation.
Structural biology driven lead optimisation
Developments in x-ray crystallography, in terms of increased ease of access, throughput, and reduced costs, have made this a key tool to drive lead optimisation of amenable targets. In one recent project, for example, structural biology data provided a profound understanding of the binding mode and key ligand-protein interactions - allowing the rapid optimisation of a weak-binding (low micromolar potency) ligand to a low nanomolar lead within 3-4 months. Structural biology studies have been carried out using the customer’s own group or by outsourcing to established partners.
The application of macrocycles and natural products to inhibit low druggability targets such as protein protein interactions is a growing area in drug discovery. Macrocycles occupy an area of chemical space in between oral small molecule drugs and biologics. Despite having physicochemical properties beyond the ‘rule of 5’, multiple orally available cell penetrable macrocycle drugs are on the market. Selcia’s capabilities include:
- Screening of macrocycle or natural product libraries using a variety of technologies (including those suitable for screening protein protein interactions)
- Structural elucidation of unknown peptides
- Medicinal chemistry and synthesis of peptide – non-peptide hybrids
- Derivatisation of macrocycles and natural products (including pro-drug strategies)
- Structural simplification: Reduction in molecular weight and number of chiral centres
- Solid phase peptide synthesis