FLIP: Towards Rational Discovery of Biased GPCR Ligands
Lead Research Organisation:
University of Oxford
Department Name: Biochemistry
People |
ORCID iD |
Philip Biggin (Principal Investigator) |
Publications
Heifetz A
(2015)
GPCR structure, function, drug discovery and crystallography: report from Academia-Industry International Conference (UK Royal Society) Chicheley Hall, 1-2 September 2014.
in Naunyn-Schmiedeberg's archives of pharmacology
Heifetz A
(2015)
Discovery of the First Selective, Nonpeptidic Orexin 2 Receptor Agonists.
in Journal of medicinal chemistry
Heifetz A
(2016)
The Fragment Molecular Orbital Method Reveals New Insight into the Chemical Nature of GPCR-Ligand Interactions.
in Journal of chemical information and modeling
Heifetz A
(2016)
Guiding lead optimization with GPCR structure modeling and molecular dynamics.
in Current opinion in pharmacology
Heifetz A
(2016)
Using the fragment molecular orbital method to investigate agonist-orexin-2 receptor interactions.
in Biochemical Society transactions
Biggin PC
(2016)
Beyond Membrane Protein Structure: Drug Discovery, Dynamics and Difficulties.
in Advances in experimental medicine and biology
Heifetz A
(2016)
Application of an Integrated GPCR SAR-Modeling Platform To Explain the Activation Selectivity of Human 5-HT2C over 5-HT2B.
in ACS chemical biology
Description | Through the project we have been developing and assessing a new tool that can give better insight into the interactions between a ligand and a receptor protein. Some of these interactions were previously underestimated (or not reported) and so our approach should be very useful in the context of evaluating more accurately how any one particular drug molecule interacts with its partner protein. In particular we have use a method called the Fragment Molecular Orbital (FMO) method which can provide a very detailed level of information on interactions between ligand and protein. |
Exploitation Route | We have shown how a new quantum mechanics approach can offer genuinely new insight into the nature of ligand-receptor interactions. Many colleagues around the world have contacted us to say that is has provided them with a new tool for drug discovery. |
Sectors | Pharmaceuticals and Medical Biotechnology |
Description | The findings from some of the work performed as part of this project are being used in within Evotec Ltd by Dr Heifetz. Clearly some of those projects are confidential so the details must remain sparse at this stage. |
First Year Of Impact | 2016 |
Sector | Pharmaceuticals and Medical Biotechnology |
Description | BI - XChem |
Amount | £248,000 (GBP) |
Organisation | Boehringer Ingelheim |
Sector | Private |
Country | Germany |
Start | 01/2019 |
End | 12/2020 |
Description | MPLS NIF FUND |
Amount | £8,420 (GBP) |
Organisation | University of Oxford |
Sector | Academic/University |
Country | United Kingdom |
Start | 02/2017 |
Title | GLAS |
Description | GLAS (GPCR Likeness Assessment Score) is an analysis tool that was developed by Dr Heifetz, prior to the award of the FLIP award. Since the award of the FLIP we have been collaborating with the CCPBioSim consortium to expand the tool for use across different HPC platforms. The explosion in the structural biology for GPCRs means that many researchers around the world are examining the dynamic behaviour of these drug targets now and new tools are required to help analyse the results. The GLAS tool provides an easy way to assess the quality of simulation structures in relation to known cyrstallographic data. |
Type Of Material | Data analysis technique |
Provided To Others? | No |
Impact | It is still in development, so we cannot assess the impact directly at this moment in time. |
URL | http://pubs.acs.org/doi/abs/10.1021/bi401119m |
Description | Biased Ligands |
Organisation | Vanderbilt University |
Country | United States |
Sector | Academic/University |
PI Contribution | We have partnered up to provide modelling insight onto structural information into biased signalling. |
Collaborator Contribution | Structural information. |
Impact | None yet - the collaboration has only formed in the past 4 months. |
Start Year | 2014 |
Description | Evotec AI |
Organisation | Evotec (UK) Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | Studentship aimed at researching the use of MD in Artificial Intelligence. |
Collaborator Contribution | None yet. |
Impact | N/A yet. |
Start Year | 2018 |
Description | Pfizer Neusentis |
Organisation | Pfizer Ltd |
Department | Neusentis Pfizer |
Country | United Kingdom |
Sector | Private |
PI Contribution | We have performed the molecular modelling on 5HT2C G-protein signalling biased agonists. In this case, we are trying to rationalize the selectivity between the 5HT2C/5HT2B receptors. |
Collaborator Contribution | The partners have matched pair assay data for a large series of compounds against both these receptors. |
Impact | There is a manuscript in preparation which will be submitted before Christmas. The collaboration is multidisciplinary and has the following disciplines:- Organic chemistry (synthesis) Computational chemistry (modelling and dynamics) Biochemistry (assays |
Start Year | 2014 |
Description | Vertex - CFTR |
Organisation | Vertex Pharmaceuticals |
Country | United States |
Sector | Private |
PI Contribution | This is a studentship that will commence in 2019. |
Collaborator Contribution | None yet., |
Impact | N/A. |
Start Year | 2019 |
Title | WaterDock |
Description | A software to predict the location of water molecules in proteins. |
Type Of Technology | Software |
Year Produced | 2016 |
Open Source License? | Yes |
Impact | N/A |
URL | https://github.com/bigginlab/WaterDock-2.0 |
Description | 5th RSC/SCI Symposium on GPCRs in Medicinal Chemistry |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | This was a poster presentation and there was much discussion afterwards about our work. This stimulated some more discussion about our approach to these problems and indeed questions of how broadly applicable they were. |
Year(s) Of Engagement Activity | 2014 |
URL | http://www.rsc.org/Membership/Networking/InterestGroups/BMCS/GPCRs2014.asp |
Description | Heifetz - Berlin meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Dr Heifetz was an international speaker at the GTC 2rd GPCR Targeted Screening Conference on GPCRs. Discussions afterwards from several industry colleagues led to new ideas and an invitation to write a review in 2016. |
Year(s) Of Engagement Activity | 2015 |
Description | Heifetz - Cambridge (UK SAR |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Dr Heifetz presented the results from our FLIP collaboration at this international conference. The talk was well-received by audience members. |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.ukqsar.org/2015/06/19/auumn-2015-meeting-6th-october-duxford/ |
Description | Heifetz - Oxford (MGMS) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Dr Heifetz presented results from our FLIP collaboration at this international meeting held in Oxford. He was an invited speaker. |
Year(s) Of Engagement Activity | 2015 |
URL | http://sbcb.bioch.ox.ac.uk/mgms2015 |
Description | Heifetz - Prato (GPCRs: Beyond Structure Towards Biochemical Society Conference Monash University Italy) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Dr Heifetz was an invited speaker at this international GPCR meeting. The invitation arose from his talk in Oxford earlier in the year. |
Year(s) Of Engagement Activity | 2015 |
URL | https://www.biochemistry.org/Events/tabid/379/MeetingNo/SA173/view/Conference/Default.aspx |
Description | Istanbul December 2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | A talk on free energy. |
Year(s) Of Engagement Activity | 2018 |