An in silico structure-based approach to map the druggable allosteric space of membrane receptors

Lead Research Organisation: Queen Mary University of London
Department Name: William Harvey Research Institute


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Technical Summary

We intend to develop a computational methodology for the search of allosteric binding sites in the membrane receptors based on the cutting-edge enhanced sampling molecular dynamics combined with smart cosolvent mapping. We will address several current limitations in cosolvent mapping for the membrane proteins: probe non-specific binding, protein denaturation, limited probe sampling, and membrane distortion. We will initially develop the computational methodology of allosteric site mapping using the M2, PAR2, CCR9 and P2Y1 receptors of Class A, and the CRF1 and GCGR receptors of Class B GPCRs with the available crystal structures of a receptor-allosteric modulator complex. We will develop approaches of assessing the functional relevance of the sites that include construction of allosteric networks, druggability assessment and sequence analysis. Next, we will apply the developed protocols to predict allosteric sites of the D3, CXCR4 and PAR1 receptors. The predicted allosteric sites will be further tested in site-directed mutagenesis. In the case of PAR1, virtual screening of compound libraries followed by experimental test will be performed to further prove the computational methodology. Using the results of cosolvent mapping together with the phylogenetic analysis we will start rationalization of allosteric site location across the GPCR family.

Planned Impact

Understanding of allosteric regulation in biomolecules is essential for in-depth comprehension of a broad range of complex biological systems under physiological conditions and in diseases, and will greatly benefit the development of more selective, potent and effective allosteric drugs. Our study of allosteric modulation in GPCRs through mapping of putative binding sites and understanding their functional relevance and location across the GPCR family will facilitate identification novel pharmacological tools to further decipher the signalling complexities of GPCRs. In addition, our work will provide a conceptual framework to study allostery in other receptor families, such as ligand- and voltage-gated ion channels, tyrosine kinases and nuclear hormone receptors.

Our computational methodology will aim to overcome the limitations of currently available protocols for MD-cosolvent mapping and to develop a complex analysis of simulation data involving application of bio/chemoinformatics tools. This will be beneficial in atomistic computer simulations of other biosystems as well as materials, nanostructures and synthetic molecules.

The findings of this research will be disseminated through publications in leading international journals and presentations at international conferences. Research staff in this project may move on to careers in the industry where they could bring in the new multidisciplinary knowledge. The protocols to carry out research will be made widely available to academic and industrial scientists via various popular science and general online resources.

Allosteric modulators of GPCRs have emerged as a novel and highly desirable class of compounds. The direct outcome of the project will be an innovative, world leading, computational methodology for the search of allosteric sites that will facilitate allosteric drug discovery. There is a clear opportunity for the future exploitation of the results by engaging pharm and biotech companies. Therefore, in the long term our work will have a potential to improve the health and productivity of UK citizens and give a positive impact on the competitiveness of the UK pharmaceutical industry.
This project is strongly aligned with the BBSRC responsive mode priorities: Healthy ageing across the life course' 'Data driven biology' 'Systems approaches to the biosciences' and 'Technology development for the biosciences'. This research will therefore contribute towards achieving BBSRC's pathways to impact.

Pupils from primary and secondary schools, undergraduate students will benefit from our research development through public lectures within Science week in local schools, Researcher's night at Ulster Museum, Northern Ireland Science Festival in Belfast. We regularly host several high school students, who were introduced to on-going research in our labs sponsored by the Nuffield Research Foundation. General public and policy makers will learn about our research on Open Days at QUB and US, popular social networking sites (LinkedIn, Twitter and Facebook).


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Description Through this work we have identified an initial chemical compound that can be further developed to be a potential drug therapy. We have now tested this compound in pre-clinical models and shown it works to reduce food intake. We have now identified three allosteric sites on three different receptors that can be exploited for drug discovery. We have fully characterized a published allosteric molecule across a range of compounds, some used in the clinic. We have identified a novel mechanism of allosteric interaction at an important drug target controlling food intake.
Exploitation Route We will continue to refine our work and try to convince investors and biotech to help us move our chemical compound into the clinic for potential drug trials. We have demonstrated that certain individuals in the population that are obese due to genetics will respond with a drug currently in the clinic, providing hope for such individuals to reduce their BMI.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

Description We have been approached by a company to see if we can apply our approaches to a target used in the agriculture business for pest control
Description Identify novel EP4 receptor agonists for the treatment of cardiac inflammation
Amount £107,727 (GBP)
Funding ID MRC0227 
Organisation Barts Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2019 
End 09/2020