Ligand-based drug discovery

 

A Conformetrix 4D-structure reveals the preferred shapes a molecule adopts in aqueous solution. Such mode structures directly relate to the bioactive conformation of a molecule (see insert, top right).

 

What this means is that once the natural ligand for a given therapeutic target has been identified, we can obtain sufficient structural data to rationally drug that target in less than a month!

 

We are currently using our technology to determine the 4D-structures of a wide range of natural ligands (e.g. peptide hormones) which target therapeutically important receptor proteins. These 4D-structures can then be used as pharmacophore templates in our cutting-edge virtual screening system, allowing us to rapidly identify new chemistry start-points for a range of GPCR and ion-channel disease targets.

 

The image below right illustrates just how powerful this ligand-based approach can be. It depicts an overlay of the mode conformers for the natural peptide ligand Ang1-7 (in yellow), with those for the former blockbuster drug Lisinopril (in blue).  

The data underlying this image not only explains why this drug works (it mimics the end of the signalling molecule that normally controls blood pressure) but it also explains the evolution of the entire ACE inhibitor field.

 

Armed with such accurate 4D-data, it becomes obvious how to improve the existing chemistry. For example, the keto-ACE inhibitors mimic the spatial orientation of the next pharmacophore (Ph4) feature on the peptide backbone. Such insight can guide QSAR analysis and focus lead optimisation to massively reduce lead development times [more].

 

We are also looking to collaborate with key players in the pharmaceutical industry, offering access to our technology on a straight CRO basis initially, (please see our Services for more information) but with a view to entering into longer-term collaborations once we have validated our technology platform with these partners.

 

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