FLIP: Towards Rational Discovery of Biased GPCR Ligands

Lead Research Organisation: University of Oxford
Department Name: Biochemistry

Abstract

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Technical Summary

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Planned Impact

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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 Advisory Committee for the Austrian Funding Agency
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
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
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