On the application of Protein-Observed NMR to Drug Discovery.
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
Alongside X-ray crystallography, NMR is one of the only techniques capable of delivering protein structural information with atomic resolution. NMR offers the advantage over X-ray that, as a free solution based technique, protein dynamics can be observed, but it is currently more limited in terms of the size of proteins that can be studied and requires that proteins can be labelled with stable isotopes (15N, 13C, 2H) which can place restrictions on the available expression systems. Nevertheless, NMR is established as an invaluable tool for identifying novel chemical starting points for new targets as it can not only confirm binding, even for very weak milli-molar Kd interactions, but also can identify the site of this interaction and report on any conformational changes either induced by, or as a pre-requisite for ligand binding.
The focus of this collaboration is to address two of the perceived shortcomings of applying NMR in early drug discovery: First that NMR experiments consume too much protein, and second that the experiments are slow to perform, being too time consuming and therefore insufficiently high throughput either to impact the Medicinal Chemistry design iteration cycle or to support fragment screening activities.
The aim of this Ph.D. studentship at Bristol University is to enable rapid delivery of information rich multidimensional NMR data to confirm the location of fragment ligand binding on GPCRs, using minimal amounts of protein but without compromising the data quality. This will be achieved by a combination of computational modelling to prioritise the most promising chemical leads and advanced mathematical non-uniform data sampling and reconstruction methods applied to the acquisition and processing of NMR data recorded using state-of the- art low volume NMR technology for samples of fragment ligand mixed with proteins of therapeutic interest in drug discovery. NMR data will be collected on a Bruker 700 MHz spectrometer located in the School of Chemistry at UoB and equipped with a 1.7 mm cryoprobe using only 35 m L of sample. Purchase of this instrument was part funded by UCB. The computational aspects of the project will then be extended to using this NMR data to further refine the positioning of this fragment in the protein binding site and will be undertaken in collaboration with the School of Biochemistry at UoB (Sessions). The studenstship will also benefit from access to UCB's extensive Structural Biology infrastructure, including NMR facilities, via the industrial placement component of the project
The focus of this collaboration is to address two of the perceived shortcomings of applying NMR in early drug discovery: First that NMR experiments consume too much protein, and second that the experiments are slow to perform, being too time consuming and therefore insufficiently high throughput either to impact the Medicinal Chemistry design iteration cycle or to support fragment screening activities.
The aim of this Ph.D. studentship at Bristol University is to enable rapid delivery of information rich multidimensional NMR data to confirm the location of fragment ligand binding on GPCRs, using minimal amounts of protein but without compromising the data quality. This will be achieved by a combination of computational modelling to prioritise the most promising chemical leads and advanced mathematical non-uniform data sampling and reconstruction methods applied to the acquisition and processing of NMR data recorded using state-of the- art low volume NMR technology for samples of fragment ligand mixed with proteins of therapeutic interest in drug discovery. NMR data will be collected on a Bruker 700 MHz spectrometer located in the School of Chemistry at UoB and equipped with a 1.7 mm cryoprobe using only 35 m L of sample. Purchase of this instrument was part funded by UCB. The computational aspects of the project will then be extended to using this NMR data to further refine the positioning of this fragment in the protein binding site and will be undertaken in collaboration with the School of Biochemistry at UoB (Sessions). The studenstship will also benefit from access to UCB's extensive Structural Biology infrastructure, including NMR facilities, via the industrial placement component of the project
People |
ORCID iD |
| Matthew Crump (Primary Supervisor) | |
| Erik Landin (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M009122/1 | 01/10/2015 | 31/03/2024 | |||
| 1800147 | Studentship | BB/M009122/1 | 01/10/2016 | 30/09/2020 | Erik Landin |
| Description | 19 F NMR has been used to study activation and inactivation of the A2A adenosine receptor. A compound with potential as an anti Parkinson's drug was found to stabilise a novel inactive state of the A2A adensone receptor that is distinct from the standard inactive state observed in the literature. Additionally observations were made regarding the confrontational ensemble in different membrane mimetic environments. |
| Exploitation Route | These findings could be used to find further drug-like compounds that inhibit the A2A receptor by stabilising a unique inactive state. This may lead to novel compound series to treat Parkinson's disease. It is also a proof of principle for using 19 F NMR to characterise the structural mechanism of action for drug-like compounds. |
| Sectors | Pharmaceuticals and Medical Biotechnology |