Probing the extraordinary bioactivity of macrocyclic natural products: privileged motifs or biosynthetic artefacts?
Lead Research Organisation:
University of Leeds
Department Name: Sch of Chemistry
Abstract
The fields of Chemical Biology and Medicinal Chemistry require collections of molecules which are likely to be biogically active. Such collections can be screened to identify small molecules which interact with biological molecules such as proteins. Such small molecules can reveal fundamental insights into biological processes and can sometimes be ultimately used to treat diseases.The grant will explore the fundamental principles which chemists can use to design collections of small molecules. Naturally occurring small molecules, known as natural products, are necessarily biologically active. Many of these molecules have large cyclic structures. This grant will explore whether this type of structure predisposes small molecules towards biological activity.A collection of natural product-like small molecules will be prepared by extending diversity-oriented chemistry which has been developed through Professor Nelson's EPSRC Advanced fellowship. Some of these molecules will have large cyclic structures, and others will not. The molecules will be screened for a broad range of biological activities. By comparing the biological profiles of the classes of molecules, we will be able to address the fundamental chemical question of whether macrocyclic molecules are fundamentally predisposed towards biological activity. In addition, the grant will encourage postdoctoral mobility between physical and life sciences, and sufficient priority for EPSRC issued to issue a recent call.
Publications
Dow M
(2017)
Modular Synthesis of Diverse Natural Product-Like Macrocycles: Discovery of Hits with Antimycobacterial Activity
in Chemistry - A European Journal
Dow M
(2012)
Towards the systematic exploration of chemical space.
in Organic & biomolecular chemistry
Nelson A
(2015)
Innovative approaches to the design and synthesis of small molecule libraries.
in Bioorganic & medicinal chemistry
Pahl A
(2023)
Morphological subprofile analysis for bioactivity annotation of small molecules.
in Cell chemical biology
Schölermann B
(2022)
Identification of Dihydroorotate Dehydrogenase Inhibitors Using the Cell Painting Assay.
in Chembiochem : a European journal of chemical biology
Description | Robust methods for the preparation of natural product-like macrocycles have been developed (an under-represented structural class in screening collections). |
Exploitation Route | Compounds based on the scaffolds have been screened by both pharmaceutical companies and academic chemical biology units. |
Sectors | Pharmaceuticals and Medical Biotechnology |
Description | Compounds based on the macrocyclic scaffolds have been evaluated for biological function through a pharmaceutical company open innovation scheme |
First Year Of Impact | 2015 |
Sector | Pharmaceuticals and Medical Biotechnology |
Description | EPSRC programme grant |
Amount | £2,700,000 (GBP) |
Funding ID | EP/N013573/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 02/2016 |
End | 01/2021 |
Description | IMI European Lead Factory |
Amount | € 1,600,000 (EUR) |
Organisation | European Molecular Biology Organisation |
Sector | Charity/Non Profit |
Country | Germany |
Start | 01/2013 |
End | 12/2017 |
Description | AZ screening |
Organisation | AstraZeneca |
Department | Research and Development AstraZeneca |
Country | United Kingdom |
Sector | Private |
PI Contribution | Screening compounds |
Collaborator Contribution | HT screening |
Impact | None yet |
Start Year | 2014 |
Description | MPI |
Organisation | Max Planck Society |
Department | Max Planck Institute for Molecular Physiology |
Country | Germany |
Sector | Academic/University |
PI Contribution | Screening compounds |
Collaborator Contribution | HT screening and follow-up biology |
Impact | None to date |
Start Year | 2014 |
Description | PPIs |
Organisation | AstraZeneca |
Country | United Kingdom |
Sector | Private |
PI Contribution | Leeds is leading an EPSRC programme grant on protein-protein interactions that involves AstraZeneca, Domainex and Northern Institute for Cancer Research |
Collaborator Contribution | Expertise, assays, other assets, collaboration, secondments |
Impact | N/A- only just started |
Start Year | 2016 |
Description | PPIs |
Organisation | Domainex |
Country | United Kingdom |
Sector | Private |
PI Contribution | Leeds is leading an EPSRC programme grant on protein-protein interactions that involves AstraZeneca, Domainex and Northern Institute for Cancer Research |
Collaborator Contribution | Expertise, assays, other assets, collaboration, secondments |
Impact | N/A- only just started |
Start Year | 2016 |
Description | PPIs |
Organisation | Newcastle University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Leeds is leading an EPSRC programme grant on protein-protein interactions that involves AstraZeneca, Domainex and Northern Institute for Cancer Research |
Collaborator Contribution | Expertise, assays, other assets, collaboration, secondments |
Impact | N/A- only just started |
Start Year | 2016 |