Initial Discovery
Initial Discovery
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To explore new molecules that target SKP2, by screening a large amount of literature, various compounds were found that had been previously determined in other studies to interact with and have an effect on the actions of the SPK2 protein.
Two of these compounds were determined by the Providence team to be the most promising.
The first of these is known as Hit A and was identified by structure-based drug design, this means that the molecule was found to "fit in" to the SPK2 protein.
The second of these hits is Hit B which was identified by structure-based design virtual screening, which is essentially a virtual form of high throughput screening.
Hit A
Hit B
Hit Optimisation
Hit Optimisation
Once we had our hits, our team of talented pharmaceutical scientists then considered how we could improve them so that they were more suitable to be utilised as drugs to treat psoriasis in humans.
For Hit A and Hit B, our optimisation strategy was to modify the ADME properties of the compounds to meet Lipinski’s Rule of Five criteria while keeping the key functional groups unchanged.
We made the original compounds more drug-like by lowering the MW and LogP while keeping the key functional structure of the compounds unchanged, as well as modifying the alert structure of them which may have an effect due to metabolism. Finally, we obtained Analogue A and Analogue B.
Changes from Hit A to Analogue A and Physicochemical Properties
Changes from Hit A to Analogue A and Physicochemical Properties
Changes from Hit B to Analogue B and Physicochemical Properties
Changes from Hit B to Analogue B and Physicochemical Properties
Lead Compound
Lead Compound
Based on the optimization strategies mentioned above, we ultimately selected Analogue B of Hit B as the lead compound. This compound not only complies with Lipinski's Rule of Five criteria but also has a smaller molecular weight and a smaller Log P compared to Analogue A, indicating improved oral absorption potential.
Technologies Used for the Development of Our Hits
Technologies Used for the Development of Our Hits
High-throughput screening
High-pressure liquid chromatography
Molecular Docking
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