Novel Polyfunctional 3D Scaffolds for Drug Discovery
Lead Research Organisation:
University of Leeds
Department Name: Sch of Chemistry
Abstract
The pharmaceutical industry relies upon the commercial availability of small polyfunctional building blocks from which to generate high quality screening libraries. The vast majority of those currently available are two-dimensional in nature, despite strong evidence that three-dimensionality is highly advantageous in drug candidates.
In this project, the chemoinformatic tool LLAMA (developed at Leeds) will be used to prioritise the synthesis of a number of novel, small, polyfunctional and highly 3D scaffolds. These compounds will then be decorated to provide small libraries of high quality fragments and screening compounds. The candidate compounds will be exposed to a range of screens to demonstrate biological relevance. Process optimisation of key compounds will be performed and, where appropriate, will be investigated for tech transfer towards commercialisation.
In this project, the chemoinformatic tool LLAMA (developed at Leeds) will be used to prioritise the synthesis of a number of novel, small, polyfunctional and highly 3D scaffolds. These compounds will then be decorated to provide small libraries of high quality fragments and screening compounds. The candidate compounds will be exposed to a range of screens to demonstrate biological relevance. Process optimisation of key compounds will be performed and, where appropriate, will be investigated for tech transfer towards commercialisation.
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/N509681/1 | 01/10/2016 | 30/09/2021 | |||
| 1939686 | Studentship | EP/N509681/1 | 01/10/2017 | 30/09/2021 | Scott Rice |
| Description | The control of molecular properties is essential in the design of new bioactive compounds, due to the inherent link between the molecular properties of lead compounds and their successful progression through the stages of clinical development. By preparing screening libraries that better target lead-like chemical space, any desirable compounds can then be grown through the optimisation stage of the drug discovery process, in terms of their molecular weight, lipophilicity and complexity to then be able to target optimal drug-like chemical space. Therefore, a set of guidelines have been established in order to better aid the design of lead-like molecules. In order to realise efficient lead-oriented synthesis, two separate "bottom-up" synthetic approaches have been employed. In both cases, simple commercially available starting materials have been functionalised to prepare cyclisation precursor molecules that contain various reaction handles in their core structure. A toolkit of cyclisation reactions has then been developed and utilised in order to cyclise between these reaction handles to prepare libraries of novel sp3-rich diverse scaffolds that are able to target lead-like chemical space. Each scaffold prepared contains between 1-3 functional handles that can be decorated to create a large number of lead-like screening compounds. At present, we have prepared two different scaffold libraries that each contain 16 final diverse 3D scaffolds. |
| Exploitation Route | The 3D scaffolds that were developed have been transferred to our industrial partners who have in turn, scaled up the chemistry to prepare these compounds at their site and have been able to sell them to other industry buyers. These compounds are now commercially available to order from or industrial collaborators. |
| Sectors | Chemicals,Pharmaceuticals and Medical Biotechnology |
| Description | A number of the final scaffold compounds that have been prepared have been transferred to our industrial partners Redbrick Molecular. Many of these compounds have also been sold to industrial buyers from Redbrick Molecular, to be used predominantly in high-throughput screening. We have also transferred experimental details and methods to Redbrick so these compounds can be made to the desired scale at their site. |
| Sector | Chemicals,Pharmaceuticals and Medical Biotechnology |