Development and application of QM/MM calculations for fragment-based drug design

Lead Research Organisation: University of Essex
Department Name: Biological Sciences

Abstract

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Technical Summary

Fragment-based drug design, FBDD, is a highly promising novel approach for

identifying lead compounds in a drug development programme10. It therefore lies

firmly within one of the 10 MRC-identified health research opportunities for focusing

strategic research, namely ?Development of new interventions?. FBDD offers efficient

screening of chemical space so that higher hit rates are obtained in the initial phases

and through careful attention to molecular properties the resulting drug candidates

should have less chance of failure later in the process. However, FBDD also poses

difficult biophysical and structural problems that need to be addressed, hence the

strategic need for this proposal. The academic partner has current BBSRC funding to

develop quantum mechanics (QM) based QM/MM methods that include molecular

mechanics (MM) polarization. He has plans for other significant improvements to

correctly address the steric repulsion between drug and enzyme using exponential

repulsion (which is essential for success in crystal structure prediction11) rather than

the computationally expedient r-12 repulsion. The industrial partner has a strong

development interest in FBDD and is interested in using QM/MM to address the

structural demands of FBDD since current docking methods are unreliable and the

interpretation of X-ray structures of bound fragments can be ambiguous. The

interchange enabled by this programme, will not only result in the development of

new tools to underpin basic FBDD research, but also offers the potential to impact

industrial and academic scientists in both institutions. Specific research goals include

(i) a thorough survey of the usefulness of QM/MM in virtual screening. (ii) An analysis

of the best way in which QM/MM with MM polarization can be used in virtual

screening. (iii) An investigation of the use of realistic repulsion in virtual screening.

(iv) An investigation in the use of QM/MM, in combination with the proposed

improvements, in interpreting ambiguous X-ray crystal structures. The applicants

have shared research goals as the industrial partner is interested in being able to

apply efficient software to FBDD while the academic partner is interested in

developing relevant computational methods that can be applied to the problem of

improving the quality of life.

9. Maurer, RI; Blower, PJ; Dilworth, JR; Reynolds, CA; Zheng, YF; Mullen, GED

Studies on the mechanism of hypoxic selectivity in copper bis(thiosemicarbazone)

radiopharmaceuticals. J. Med. Chem. 2002, 45, 1420-1431.

10. Congreve, M; Chessari, G; Tisi, D; Woodhead, AJ. Recent developments in

fragment-based drug discovery. J. Med. Chem 2008, 51, 3661-3680.

5

11. Misquitta, AJ; Welch, GWA; Stone, AJ; Price, S. L. A first principles prediction of

the crystal structure of C6Br2ClFH2. Chem. Phys. Lett. 2008, 456, 105-109.

12. Jorgensen, WL Special issue on polarization. J. Chem. Theory Comput. 2007, 3,

1877.

13. Mura, ME; Knowles, PJ; Reynolds, CA Accurate numerical determination of Kohn-

Sham potentials from electronic densities .1. Two-electron systems. J. Chem. Phys.

1997, 106, 9659-9667.

Publications

10 25 50
 
Description HPC Europa2 transnational visit: Taddese
Amount € 2,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 07/2012 
End 12/2012
 
Description HPC-Europa2 transnational visit: Reynolds
Amount € 2,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 07/2012 
End 12/2012
 
Description Pancreatic cancer UK
Amount £74,285 (GBP)
Funding ID RPG-2017-255 
Organisation Pancreatic Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2017 
End 02/2018
 
Description Responsive mode
Amount £1 (GBP)
Funding ID Email from BBSRC to say that the grant will be announced in due course 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2015 
End 12/2016
 
Title GLP-1R 
Description Computer models have been generated of the GLP-1 receptor, the adrenomedullin receptor and the PTH2 receptor; these have been validated by collaborative experimental studies. The models are available from ftp.essex.ac.uk/pub/oyster/ 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact The models have had a significant impact on explaining pharmacological data on important drug targets, as indicated in the following publications: 1. Wotten, D., Reynolds, C. A., Smith, K. J., Mobarec, J. C., Koole, C., Savage, E. E., Pabreja, K., Simms, J., Sridhar, R., and Furness, S. G., Miller, L. J., Christopoulos, A., and Sexton, P. M. (2016) The extracellular surface of the GLP-1 receptor is a molecular trigger for biased agonism. Cell 165,1632-1643. doi.org/10.1016/j.cell.2016.05.023 2. Wootten, D., Reynolds, C. A., Smith, K. J., Mobarec, J. C., Furness, S. G., Miller, L. J., Christopoulos, A., and Sexton, P. M. (2016) Key interactions by conserved polar amino acids located at the transmembrane helical boundaries in Class B GPCRs modulate activation, effector specificity and biased signalling in the glucagon-like peptide-1 receptor. Biochem. Pharmacol. 118,68-87. doi.org/10.1016/j.bcp.2016.08.015 3. Wootten, D., Reynolds, C. A., Koole, C., Smith, K. J., Mobarec, J. C., Simms, J., Quon, T., Coudrat, T., Furness, S. G., and Miller, L. J. (2016) A hydrogen-bonded polar network in the core of the glucagon-like peptide-1 receptor is a fulcrum for biased agonism: lessons from class B crystal structures. Mol. Pharmacol. 89,335-347. doi.org/10.1124/mol.115.101246 4. Weston, C., Winfield, I., Harris, M., Hodgson, R., Shah, A., Dowell, S. J., Mobarec, J. C., Woodlock, D. A., Reynolds, C. A., and Poyner, D. R. (2016) Receptor Activity-modifying Protein-directed G Protein Signaling Specificity for the Calcitonin Gene-related Peptide Family of Receptors. J. Biol. Chem. 291,21925-21944. doi.org/10.1074/jbc.M116.751362 5. Weaver, R. E., Mobarec, J. C., Wigglesworth, M. J., Reynolds, C. A., and Donnelly, D. (2016) High affinity binding of the peptide agonist TIP-39 to the parathyroid hormone 2 (PTH 2) receptor requires the hydroxyl group of Tyr-318 on transmembrane helix 5. Biochem. Pharmacol. doi.org/10.1016/j.bcp.2016.12.013 6. Watkins, H. A., Chakravarthy, M., Abhayawardana, R. S., Gingell, J. J., Garelja, M., Pardamwar, M., McElhinney, J. M., Lathbridge, A., Constantine, A., and Harris, P. W. (2016) Receptor Activity-modifying Proteins 2 and 3 Generate Adrenomedullin Receptor Subtypes with Distinct Molecular Properties. J. Biol. Chem. 291,11657-11675. doi.org/10.1074/jbc.M115.688218 
URL http://ftp.essex.ac.uk/pub/oyster/
 
Description Biased signalling in the GLP1 receptor 
Organisation Mayo Clinic
Department Molecular Pharmacology and Experimental Therapeutics
Country United States 
Sector Hospitals 
PI Contribution homology Modelling the GLP1 receptor; molecular dynamics studies of the GLP1 receptor; docking studies on ligands binding to the receptor
Collaborator Contribution Experimental mutagenesis studies of the GLP1 receptor and an analysis of the preferred signalling pathways of the receptor in the presence of various agonists, namely GLP1 peptide, oxyntmodulin and exendin-4
Impact Wootten, D.; Reynolds, C. A.; Koole, C.; Smith, K. J.; Mobarec, J. C.; Quon, T.; Coudrat, T.; Furness, S. G. B.; Miller, L. J.; Christopoulos, A.; Sexton, P. M. A hydrogen-bonded polar network in the core of the glucagon-like peptide-1 receptor is a fulcrum for biased agonism: lessons from class B crystal structures. Mol. Pharmacol. (resubmitted) 2016, 89, 335-347
Start Year 2015
 
Description Biased signalling in the GLP1 receptor 
Organisation Monash University
Country Australia 
Sector Academic/University 
PI Contribution homology Modelling the GLP1 receptor; molecular dynamics studies of the GLP1 receptor; docking studies on ligands binding to the receptor
Collaborator Contribution Experimental mutagenesis studies of the GLP1 receptor and an analysis of the preferred signalling pathways of the receptor in the presence of various agonists, namely GLP1 peptide, oxyntmodulin and exendin-4
Impact Wootten, D.; Reynolds, C. A.; Koole, C.; Smith, K. J.; Mobarec, J. C.; Quon, T.; Coudrat, T.; Furness, S. G. B.; Miller, L. J.; Christopoulos, A.; Sexton, P. M. A hydrogen-bonded polar network in the core of the glucagon-like peptide-1 receptor is a fulcrum for biased agonism: lessons from class B crystal structures. Mol. Pharmacol. (resubmitted) 2016, 89, 335-347
Start Year 2015
 
Description CGRP antagonists 
Organisation Aston University
Country United Kingdom 
Sector Academic/University 
PI Contribution Modelling interactions of ligands with the CGRP receptor and other proteins.
Collaborator Contribution Pharmonovo supply ligands and coordinate the project David Kendall, PhD, Professor of Pharmacology, University of Nottingham; in vitro investigations of receptor activity and behavioural evaluation of novel compounds in animal models. Over 30 years of experience of GPCR pharmacology. OnTarget Chemistry. Fredrik Lehmann: synthetic chemistry University of Reading. Graeme Cottrell, PhD, Lecturer in Cellular and Molecular Neuroscience; In vitro investigations of the effects of novel compounds on CGRP trafficking and signalling; Over 10 year experience in GPCR trafficking and signalling University of Aston. David Poyner, PhD, Professor of Pharmacology. Mapping antagonist binding sites on the CGRP receptor. 25 year experience of studying the CGRP receptor. University of Essex, Mike Hough, X-ray crystallography Kings College, London. Susan Brain, PhD, Professor of Pharmacology, Vascular Biology and Inflammation. In vivo measurements of blood flow in murine models, especially in first pre-clinical experiments to determine potency, mode of administration and duration of action. PharmInVivo. Zsuzsanna Helyes, MD, PhD, DSc. PharmInVivo is a spin-out based in the Department of Pharmacology and Pharmacotherapy at the Medical Faculty & Szentagothai Research Center of the University of Pécs. She has worked in the fields of pain and inflammation for decades and has great expertise in a variety of experimental models with special emphasis on in vivo studies.
Impact This is a new multi-disciplinary collaboration that has submitted a grant application to the Wellcome Trust, which was not funded. Discussions within this consortium helped Poyner and Reynolds to submit a successful grant on CGRP.
Start Year 2013
 
Description CGRP antagonists 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Modelling interactions of ligands with the CGRP receptor and other proteins.
Collaborator Contribution Pharmonovo supply ligands and coordinate the project David Kendall, PhD, Professor of Pharmacology, University of Nottingham; in vitro investigations of receptor activity and behavioural evaluation of novel compounds in animal models. Over 30 years of experience of GPCR pharmacology. OnTarget Chemistry. Fredrik Lehmann: synthetic chemistry University of Reading. Graeme Cottrell, PhD, Lecturer in Cellular and Molecular Neuroscience; In vitro investigations of the effects of novel compounds on CGRP trafficking and signalling; Over 10 year experience in GPCR trafficking and signalling University of Aston. David Poyner, PhD, Professor of Pharmacology. Mapping antagonist binding sites on the CGRP receptor. 25 year experience of studying the CGRP receptor. University of Essex, Mike Hough, X-ray crystallography Kings College, London. Susan Brain, PhD, Professor of Pharmacology, Vascular Biology and Inflammation. In vivo measurements of blood flow in murine models, especially in first pre-clinical experiments to determine potency, mode of administration and duration of action. PharmInVivo. Zsuzsanna Helyes, MD, PhD, DSc. PharmInVivo is a spin-out based in the Department of Pharmacology and Pharmacotherapy at the Medical Faculty & Szentagothai Research Center of the University of Pécs. She has worked in the fields of pain and inflammation for decades and has great expertise in a variety of experimental models with special emphasis on in vivo studies.
Impact This is a new multi-disciplinary collaboration that has submitted a grant application to the Wellcome Trust, which was not funded. Discussions within this consortium helped Poyner and Reynolds to submit a successful grant on CGRP.
Start Year 2013
 
Description CGRP antagonists 
Organisation OnTarget Chemistry
Country Sweden 
Sector Private 
PI Contribution Modelling interactions of ligands with the CGRP receptor and other proteins.
Collaborator Contribution Pharmonovo supply ligands and coordinate the project David Kendall, PhD, Professor of Pharmacology, University of Nottingham; in vitro investigations of receptor activity and behavioural evaluation of novel compounds in animal models. Over 30 years of experience of GPCR pharmacology. OnTarget Chemistry. Fredrik Lehmann: synthetic chemistry University of Reading. Graeme Cottrell, PhD, Lecturer in Cellular and Molecular Neuroscience; In vitro investigations of the effects of novel compounds on CGRP trafficking and signalling; Over 10 year experience in GPCR trafficking and signalling University of Aston. David Poyner, PhD, Professor of Pharmacology. Mapping antagonist binding sites on the CGRP receptor. 25 year experience of studying the CGRP receptor. University of Essex, Mike Hough, X-ray crystallography Kings College, London. Susan Brain, PhD, Professor of Pharmacology, Vascular Biology and Inflammation. In vivo measurements of blood flow in murine models, especially in first pre-clinical experiments to determine potency, mode of administration and duration of action. PharmInVivo. Zsuzsanna Helyes, MD, PhD, DSc. PharmInVivo is a spin-out based in the Department of Pharmacology and Pharmacotherapy at the Medical Faculty & Szentagothai Research Center of the University of Pécs. She has worked in the fields of pain and inflammation for decades and has great expertise in a variety of experimental models with special emphasis on in vivo studies.
Impact This is a new multi-disciplinary collaboration that has submitted a grant application to the Wellcome Trust, which was not funded. Discussions within this consortium helped Poyner and Reynolds to submit a successful grant on CGRP.
Start Year 2013
 
Description CGRP antagonists 
Organisation Pharmnovo AB/Pharmnovo UK Ltd
Country Sweden 
Sector Private 
PI Contribution Modelling interactions of ligands with the CGRP receptor and other proteins.
Collaborator Contribution Pharmonovo supply ligands and coordinate the project David Kendall, PhD, Professor of Pharmacology, University of Nottingham; in vitro investigations of receptor activity and behavioural evaluation of novel compounds in animal models. Over 30 years of experience of GPCR pharmacology. OnTarget Chemistry. Fredrik Lehmann: synthetic chemistry University of Reading. Graeme Cottrell, PhD, Lecturer in Cellular and Molecular Neuroscience; In vitro investigations of the effects of novel compounds on CGRP trafficking and signalling; Over 10 year experience in GPCR trafficking and signalling University of Aston. David Poyner, PhD, Professor of Pharmacology. Mapping antagonist binding sites on the CGRP receptor. 25 year experience of studying the CGRP receptor. University of Essex, Mike Hough, X-ray crystallography Kings College, London. Susan Brain, PhD, Professor of Pharmacology, Vascular Biology and Inflammation. In vivo measurements of blood flow in murine models, especially in first pre-clinical experiments to determine potency, mode of administration and duration of action. PharmInVivo. Zsuzsanna Helyes, MD, PhD, DSc. PharmInVivo is a spin-out based in the Department of Pharmacology and Pharmacotherapy at the Medical Faculty & Szentagothai Research Center of the University of Pécs. She has worked in the fields of pain and inflammation for decades and has great expertise in a variety of experimental models with special emphasis on in vivo studies.
Impact This is a new multi-disciplinary collaboration that has submitted a grant application to the Wellcome Trust, which was not funded. Discussions within this consortium helped Poyner and Reynolds to submit a successful grant on CGRP.
Start Year 2013
 
Description CGRP antagonists 
Organisation University of Nottingham
Department School of Biomedical Sciences Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Modelling interactions of ligands with the CGRP receptor and other proteins.
Collaborator Contribution Pharmonovo supply ligands and coordinate the project David Kendall, PhD, Professor of Pharmacology, University of Nottingham; in vitro investigations of receptor activity and behavioural evaluation of novel compounds in animal models. Over 30 years of experience of GPCR pharmacology. OnTarget Chemistry. Fredrik Lehmann: synthetic chemistry University of Reading. Graeme Cottrell, PhD, Lecturer in Cellular and Molecular Neuroscience; In vitro investigations of the effects of novel compounds on CGRP trafficking and signalling; Over 10 year experience in GPCR trafficking and signalling University of Aston. David Poyner, PhD, Professor of Pharmacology. Mapping antagonist binding sites on the CGRP receptor. 25 year experience of studying the CGRP receptor. University of Essex, Mike Hough, X-ray crystallography Kings College, London. Susan Brain, PhD, Professor of Pharmacology, Vascular Biology and Inflammation. In vivo measurements of blood flow in murine models, especially in first pre-clinical experiments to determine potency, mode of administration and duration of action. PharmInVivo. Zsuzsanna Helyes, MD, PhD, DSc. PharmInVivo is a spin-out based in the Department of Pharmacology and Pharmacotherapy at the Medical Faculty & Szentagothai Research Center of the University of Pécs. She has worked in the fields of pain and inflammation for decades and has great expertise in a variety of experimental models with special emphasis on in vivo studies.
Impact This is a new multi-disciplinary collaboration that has submitted a grant application to the Wellcome Trust, which was not funded. Discussions within this consortium helped Poyner and Reynolds to submit a successful grant on CGRP.
Start Year 2013
 
Description CGRP antagonists 
Organisation University of Pecs
Department Department of Pharmacology and Pharmacotherapy
PI Contribution Modelling interactions of ligands with the CGRP receptor and other proteins.
Collaborator Contribution Pharmonovo supply ligands and coordinate the project David Kendall, PhD, Professor of Pharmacology, University of Nottingham; in vitro investigations of receptor activity and behavioural evaluation of novel compounds in animal models. Over 30 years of experience of GPCR pharmacology. OnTarget Chemistry. Fredrik Lehmann: synthetic chemistry University of Reading. Graeme Cottrell, PhD, Lecturer in Cellular and Molecular Neuroscience; In vitro investigations of the effects of novel compounds on CGRP trafficking and signalling; Over 10 year experience in GPCR trafficking and signalling University of Aston. David Poyner, PhD, Professor of Pharmacology. Mapping antagonist binding sites on the CGRP receptor. 25 year experience of studying the CGRP receptor. University of Essex, Mike Hough, X-ray crystallography Kings College, London. Susan Brain, PhD, Professor of Pharmacology, Vascular Biology and Inflammation. In vivo measurements of blood flow in murine models, especially in first pre-clinical experiments to determine potency, mode of administration and duration of action. PharmInVivo. Zsuzsanna Helyes, MD, PhD, DSc. PharmInVivo is a spin-out based in the Department of Pharmacology and Pharmacotherapy at the Medical Faculty & Szentagothai Research Center of the University of Pécs. She has worked in the fields of pain and inflammation for decades and has great expertise in a variety of experimental models with special emphasis on in vivo studies.
Impact This is a new multi-disciplinary collaboration that has submitted a grant application to the Wellcome Trust, which was not funded. Discussions within this consortium helped Poyner and Reynolds to submit a successful grant on CGRP.
Start Year 2013
 
Description CGRP antagonists 
Organisation University of Reading
Department School of Pharmacy Reading
Country United Kingdom 
Sector Academic/University 
PI Contribution Modelling interactions of ligands with the CGRP receptor and other proteins.
Collaborator Contribution Pharmonovo supply ligands and coordinate the project David Kendall, PhD, Professor of Pharmacology, University of Nottingham; in vitro investigations of receptor activity and behavioural evaluation of novel compounds in animal models. Over 30 years of experience of GPCR pharmacology. OnTarget Chemistry. Fredrik Lehmann: synthetic chemistry University of Reading. Graeme Cottrell, PhD, Lecturer in Cellular and Molecular Neuroscience; In vitro investigations of the effects of novel compounds on CGRP trafficking and signalling; Over 10 year experience in GPCR trafficking and signalling University of Aston. David Poyner, PhD, Professor of Pharmacology. Mapping antagonist binding sites on the CGRP receptor. 25 year experience of studying the CGRP receptor. University of Essex, Mike Hough, X-ray crystallography Kings College, London. Susan Brain, PhD, Professor of Pharmacology, Vascular Biology and Inflammation. In vivo measurements of blood flow in murine models, especially in first pre-clinical experiments to determine potency, mode of administration and duration of action. PharmInVivo. Zsuzsanna Helyes, MD, PhD, DSc. PharmInVivo is a spin-out based in the Department of Pharmacology and Pharmacotherapy at the Medical Faculty & Szentagothai Research Center of the University of Pécs. She has worked in the fields of pain and inflammation for decades and has great expertise in a variety of experimental models with special emphasis on in vivo studies.
Impact This is a new multi-disciplinary collaboration that has submitted a grant application to the Wellcome Trust, which was not funded. Discussions within this consortium helped Poyner and Reynolds to submit a successful grant on CGRP.
Start Year 2013
 
Description CGRP collaboration 
Organisation Aston University
Country United Kingdom 
Sector Academic/University 
PI Contribution Bioinformatics, Docking, Comparative Modelling, Molecular Modelling, Molecular Dynamics simulation
Collaborator Contribution Experimental site-directed mutagenesis, cell biology, pharmacology
Impact Multi-disciplinary: (i) cell-biology/pharmacology (ii) computational chemistry / structural bioinformatics PMID: 24047872 PMID: 23356280 PMID: 23235263
Start Year 2012
 
Description CGRP collaboration 
Organisation University of Auckland
Country New Zealand 
Sector Academic/University 
PI Contribution Bioinformatics, Docking, Comparative Modelling, Molecular Modelling, Molecular Dynamics simulation
Collaborator Contribution Experimental site-directed mutagenesis, cell biology, pharmacology
Impact Multi-disciplinary: (i) cell-biology/pharmacology (ii) computational chemistry / structural bioinformatics PMID: 24047872 PMID: 23356280 PMID: 23235263
Start Year 2012
 
Description CGRP collaboration 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Bioinformatics, Docking, Comparative Modelling, Molecular Modelling, Molecular Dynamics simulation
Collaborator Contribution Experimental site-directed mutagenesis, cell biology, pharmacology
Impact Multi-disciplinary: (i) cell-biology/pharmacology (ii) computational chemistry / structural bioinformatics PMID: 24047872 PMID: 23356280 PMID: 23235263
Start Year 2012
 
Description CGRP collaboration 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Bioinformatics, Docking, Comparative Modelling, Molecular Modelling, Molecular Dynamics simulation
Collaborator Contribution Experimental site-directed mutagenesis, cell biology, pharmacology
Impact Multi-disciplinary: (i) cell-biology/pharmacology (ii) computational chemistry / structural bioinformatics PMID: 24047872 PMID: 23356280 PMID: 23235263
Start Year 2012
 
Description Closed Loops 
Organisation National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS)
Country France 
Sector Public 
PI Contribution Protein modelling, statistics
Collaborator Contribution coarse-grain elastic network simulations
Impact Chintapalli, S. V.; Illingworth, C. J.; Upton, G. J.; Sacquin-Mora, S.; Reeves, P. J.; Mohammedali, H. S.; Reynolds, C. A. Assessing the effect of dynamics on the closed-loop protein-folding hypothesis. J R. Soc Interface 2014, 11 (91), 20130935. PMID: 24258160, doi: 10.1098/rsif.2013.0935
Start Year 2012
 
Description Glucagon and GLP-1 receptor 
Organisation Aston University
Country United Kingdom 
Sector Academic/University 
PI Contribution Molecular modelling: interactions between peptide ligand and receptor
Collaborator Contribution Yeast Cell Biology (Ladds, Warwick until mid 2015; now Cambridge); Pharmacology (Poyner, Aston)
Impact multi-disciplinary: (i) cell biology (Warwick), (ii) pharmacology (Aston), (iii) computational chemistry (comparative modelling, docking, Essex) Publication in preparation, entitled 'Modulation of glucagon receptor pharmacology by RAMP2', by Weston, C., Lu, J., Richards, G. O., Roberts, D. J., Skerry, T. M., Dowell, S. J., Willars, G. B., Reynolds C.A. and Ladds, G. Grant Application on biased signalling in the GLP-1 receptor in preparation (with G. Ladds, D.R. Poyner).
Start Year 2014
 
Description Glucagon and GLP-1 receptor 
Organisation University of Cambridge
Department Department of Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution Molecular modelling: interactions between peptide ligand and receptor
Collaborator Contribution Yeast Cell Biology (Ladds, Warwick until mid 2015; now Cambridge); Pharmacology (Poyner, Aston)
Impact multi-disciplinary: (i) cell biology (Warwick), (ii) pharmacology (Aston), (iii) computational chemistry (comparative modelling, docking, Essex) Publication in preparation, entitled 'Modulation of glucagon receptor pharmacology by RAMP2', by Weston, C., Lu, J., Richards, G. O., Roberts, D. J., Skerry, T. M., Dowell, S. J., Willars, G. B., Reynolds C.A. and Ladds, G. Grant Application on biased signalling in the GLP-1 receptor in preparation (with G. Ladds, D.R. Poyner).
Start Year 2014
 
Description Glucagon and GLP-1 receptor 
Organisation University of Warwick
Department Warwick Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution Molecular modelling: interactions between peptide ligand and receptor
Collaborator Contribution Yeast Cell Biology (Ladds, Warwick until mid 2015; now Cambridge); Pharmacology (Poyner, Aston)
Impact multi-disciplinary: (i) cell biology (Warwick), (ii) pharmacology (Aston), (iii) computational chemistry (comparative modelling, docking, Essex) Publication in preparation, entitled 'Modulation of glucagon receptor pharmacology by RAMP2', by Weston, C., Lu, J., Richards, G. O., Roberts, D. J., Skerry, T. M., Dowell, S. J., Willars, G. B., Reynolds C.A. and Ladds, G. Grant Application on biased signalling in the GLP-1 receptor in preparation (with G. Ladds, D.R. Poyner).
Start Year 2014
 
Description Industry Interchange 
Organisation GlaxoSmithKline (GSK)
Department Discovery Partnerships with Academia
Country Global 
Sector Private 
PI Contribution Novel QM/MM methods that include a polarizable MM region for application to fragment-based drug design (FBDD)
Collaborator Contribution Advice in how to apply these methods to FBDD
Impact See publications involving Ian Wall
Start Year 2010
 
Description Modelling polarization 
Organisation University of South Bohemia
Country Czech Republic 
Sector Academic/University 
PI Contribution Intellectual input, computing resources and programming skills
Collaborator Contribution Intellectual input, computing resources and programming skills, with an emphasis on quantum chemistry and programing.
Impact Polarized docking software
Start Year 2011
 
Description Yeast Pheramone Receptors: similarity to mamalian GPCRs 
Organisation University of Warwick
Department Warwick Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution Molecular Modelling receptor structure based on a novel approach to aligning sequences in or below the twilight zone; docking peptide ligands to the receptor
Collaborator Contribution Cell Biology, random and site-directed mutagenesis, pharmacology
Impact Multi-disciplinary: (i) cell biology, (ii) computational chemistry/ docking /structural bioinformatics. A draft manuscript is in preparation entitled: 'Towards a molecular level understanding of yeast pheromone receptors' by Graham Ladds, Graham J.G. Upton, Hugh R. Allen, Asil M. Amin, Liam Davidson-Gates, Jack Sawyer, Sophie Smith, and Christopher A Reynolds
Start Year 2014
 
Title Sequence alignment software 
Description Software for aligning remote homologues, i.e. the software can, in favourabel circumstances, be used to align profiles where the mean percentage identity is below the 18-25% that makes alignment almost impossible. 
Type Of Technology Software 
Year Produced 2013 
Impact The software has been used to align GCR1 homologues to class A, class B and class F GPCRs and hence show that plants contain GPCRs - or at least that they contain GPCR motifs, as shown in Taddese et al., PlantPhys, 2014, PMID 24246381. The software can also be used to align and hence dock pharmaceutically important peptide ligands, as will be shown in Weaver et al., in preparation (collaboration with D. Donnelly) and Weston et al., (collaboration with G. Ladds). Resources will be sought, e.g. from BBSRC, to enhance this software and to make it available as a web server. 
 
Title polarization software 
Description The search for a new drug may start on the computer by 'docking' potential molecules into a structure of the drug target, which is typically an enzyme or a receptor. Molecules that are calculated to fit well can therefore be made and tested experimentally, while those calculated to have a poor fit can be ignored, thus saving time and expense. However, these calculations do not always work well. These calculations usually assumes that the atomic charge distribution on the molecule and the enzyme does not change when the molecule approaches the enzyme even when the charges on some of the atoms are quite high and might therefore affect each other, i.e. one molecule might polarize the other. We have developed a method of including enzyme polarization and ligand polarization in docking that can be combined with standard state-of-the art docking software, e.g. Glide. This should greatly reduce one of the main errors in docking. The method is based on a series of Perl scripts and converts an induced dipole to a set of induced charges. The induced dipole can be calculated classically, or quantum mechanically. Typically the induced dpole at the enzyme is calculated from the ligand quantum mechanical electrostatic potential at the atoms of the enzyme. 
Type Of Technology Software 
Year Produced 2011 
Open Source License? Yes  
Impact Inclusion of polarization by this method typically halves the proportion of compounds incorrectly docked using GLIDE, a state-of the art docking program and therefore has the potential to facilitate the drug design process. This is particularly true when appropriate water molecules are included as part of the enzyme target. 
URL http://ftp://ftp.essex.ac.uk/pub/oyster/polarization
 
Description Drug Design Workshop for the giften and able 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 8 Gifted and able students from Bromfords School, Essex, attended a week-long drug design workshop, which greatly increased the pupils enthusiasm for science.
Year(s) Of Engagement Activity 2016