Harnessing Our Understanding Of Water To Identify Druggable Protein Targets and Drive The Development Of Effective Therapeutics

Lead Research Organisation: University of Cambridge
Department Name: Physics

Abstract

Drug development is an extraordinarily expensive and lengthy process. Recent estimates suggest that the total cost of developing one new drug are steadily increasing and will soon reach £1.5 billion. The timescale for a successful project is 12-15 years. However, success rates in drug development are currently falling. Sensible choices early in the process of drug development are thus vital and can lead to huge cost savings and improved outcomes for patients. The first two steps on the path to developing a new drug are:

(1) Identifying a biological target that is suitable for drug design and will lead to effective therapies.
(2) Determining which chemical compounds are best able to inhibit this biological target to combat disease.

The task of finding suitable biological targets and chemical compounds can be made quicker and more efficient by combining an understanding of the physical basis of disease with powerful computer models. These computer models can aid in the identification of biological targets that will prove fruitful in drug development projects and design compounds whose shapes are most complementary to the shapes of the targeted proteins. This project will use such computer models to increase the effectiveness of both of the stages above, resulting in shorter lead times and fewer dead ends in drug development. This will provide great benefit to society, which must eventually pay the cost of drug development. The project will increase efficiency by utilising the enormous amount of data on the shapes of proteins that has already been collected. Identifying biological targets that are suitable for drug design will be achieved by developing a computer model utilising such data on the shapes of proteins. The results of these calculations will be disseminated via a purpose-built website to allow academic groups and drugs companies to focus their efforts on developing effective treatments. Determining chemical compounds that are able to inhibit specific iological targets will be achieved by collaborating with existing drug development projects at the University of Cambridge, the Medical Research Council Technology arm and other academic and governmental institutes. My contribution will be to develop and optimise software that can design molecules with a higher affinity for their biological target and thus a greater ability to combat diseases. A number of companies sell such software, but it is prohibitively expensive for use in academic work.

My work during the fellowship will focus on a number of key improvements. Existing methods suffer from a number of approximations and do not take advantage of the constant and rapid increase in computer power. The new software will incorporate new theories to circumvent these approximations and will employ the latest computational methods to model the flexibility of proteins and the water molecules that mediate important interactions. The final outcome of this project will be a validated method to improve effectiveness in the development of new medicines. Collaborations with biology and chemistry laboratories will produce the experimental results necessary to test and improve the predictions. This will directly impact the development of therapeutics for diseases such as cancer, malaria and tuberculosis. The improvements in theory and methodology will be very useful within this important field and the software will be freely available to university researchers, extending its value beyond the length of the project. The proposed project will identify new biological targets and generate new chemical compounds to treat disease, benefiting society in the fight against disease.

Technical Summary

Water is the most important molecule in biology. The interaction between any two biological molecules must compete with the interactions of the individual molecules with water and thus it is involved in every single intermolecular interaction in an aqueous environment. This also makes water the most important molecule in medicine, as it controls the interactions of every therapeutic with its target. In order to account for hydration thermodynamics, this proposal is focused on inhomogeneous fluid solvation theory (IFST), a statistical mechanical method to determine the enthalpy and entropy of solvation. IFST has a number of advantages that make it superior to many of its alternatives. Explicitly including the thermodynamics of interfacial water molecules is vital, as the subtle balance of enthalpy and entropy means that immobilising a water can favour or disfavour binding. In addition, visualisation of the contributions of spatial subvolumes is a revolutionary approach that transforms the way in which water is viewed, understood and harnessed. The combination of accuracy with elucidative results, calculable on a reasonable timescale, makes IFST a powerful method for studying hydration. Novel extensions to the theory developed in this project will allow computation of binding free energies. IFST will then be used to solve two fundamental problems in drug discovery: the identification of druggable targets and the design of small molecule inhibitors. After validation, the software will be used to identify protein targets containing hot spots suitable for small molecule binding. IFST will also be combined with a molecular design algorithm that incorporates the contributions of structural waters. Collaborations with experimental groups in Cambridge and at the MRCT will allow the software to be applied directly to active drug development projects. These two advances will increase the cost effectiveness of drug development and thus support one of the UK's key industries.

Planned Impact

Drug development is an extraordinarily expensive and lengthy process. Recent estimates suggest that the total cost of developing one new drug are steadily increasing and will soon reach £1.5 billion. The timescale for a successful project is 12-15 years. However, success rates in drug development are currently falling. Sensible choices early in the process of drug development are thus vital and can lead to huge cost savings and improved outcomes for patients. The first two steps on the path to developing a new drug are:

(1) Identifying a biological target that is suitable for drug design and will lead to effective therapies.
(2) Determining which chemical compounds are best able to inhibit this biological target to combat disease.

The task of finding suitable biological targets and chemical compounds can be made quicker and more efficient by combining an understanding of the physical basis of disease with powerful computer models. These computer models can aid in the identification of biological targets that will prove fruitful in drug development projects and design compounds whose shapes are most complementary to the shapes of the targeted proteins. This project will use such computer models to increase the effectiveness of both of the stages above, resulting in shorter lead times and fewer dead ends in drug development. This will provide great benefit to society, which must eventually pay the cost of drug development. The project will increase efficiency by utilising the enormous amount of data on the shapes of proteins that has already been collected. Identifying biological targets that are suitable for drug design will be achieved by developing a computer model utilising such data on the shapes of proteins. The results of these calculations will be disseminated via a purpose-built website to allow academic groups and drugs companies to focus their efforts on developing effective treatments. Determining chemical compounds that are able to inhibit specific iological targets will be achieved by collaborating with existing drug development projects at the University of Cambridge, the Medical Research Council Technology arm and other academic and governmental institutes. My contribution will be to develop and optimise software that can design molecules with a higher affinity for their biological target and thus a greater ability to combat diseases. A number of companies sell such software, but it is prohibitively expensive for use in academic work.

My work during the fellowship will focus on a number of key improvements. Existing methods suffer from a number of approximations and do not take advantage of the constant and rapid increase in computer power. The new software will incorporate new theories to circumvent these approximations and will employ the latest computational methods to model the flexibility of proteins and the water molecules that mediate important interactions. The final outcome of this project will be a validated method to improve effectiveness in the development of new medicines. Collaborations with biology and chemistry laboratories will produce the experimental results necessary to test and improve the predictions. This will directly impact the development of therapeutics for diseases such as cancer, malaria and tuberculosis. The improvements in theory and methodology will be very useful within this important field and the software will be freely available to university researchers, extending its value beyond the length of the project. The proposed project will identify new biological targets and generate new chemical compounds to treat disease, benefiting society in the fight against disease.

Publications

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Huggins D (2019) Biomolecular simulations: From dynamics and mechanisms to computational assays of biological activity in Wiley Interdisciplinary Reviews: Computational Molecular Science

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Huggins DJ (2014) Estimating Translational and Orientational Entropies Using the k-Nearest Neighbors Algorithm. in Journal of chemical theory and computation

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Irwin B (2018) Prediction of GABARAP interaction with the GABA type A receptor in Proteins: Structure, Function, and Bioinformatics

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Irwin BWJ (2018) Estimating Atomic Contributions to Hydration and Binding Using Free Energy Perturbation. in Journal of chemical theory and computation

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Irwin BWJ (2019) Large-Scale Study of Hydration Environments through Hydration Sites. in The journal of physical chemistry. B

 
Description Alan Turing Institute Scoping Workshop
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description CCPBioSim Committee Membership
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
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Description HECBioSim Committee Membership
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
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Policy Influence Type Participation in a advisory committee
 
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Organisation Engineering and Physical Sciences Research Council (EPSRC) 
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Start 02/2015 
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Description Aurora A - Chemistry 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Computational design of small molecule inhibitors of Aurora A kinase
Collaborator Contribution Synthesis and testing of small molecule inhibitors of Aurora A kinase
Impact Molecules designed, synthesised and assayed. Publication submitted to Nature Methods.
Start Year 2014
 
Description Aurora A - SDDI 
Organisation University of Cambridge
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Identification of optimal small-molecule binding site for Aurora A target
Collaborator Contribution Synthesis, testing, and crystallography.
Impact Successful Wellcome Trust SDDI project.
Start Year 2015
 
Description Ayoub 
Organisation Technion - Israel Institute of Technology
Country Israel 
Sector Academic/University 
PI Contribution Analysis of JMJC proteins. Computational design of dominant negative mutants. Computational design of photoactive traps.
Collaborator Contribution Protein expression and testing.
Impact Publication in PNAS.
Start Year 2014
 
Description Bornemann TB 
Organisation John Innes Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of protein targets to predict ligandability and identify binding sites.
Collaborator Contribution Expertise in Mtb targets
Impact Mtb targets included in funding applications for target validation.
Start Year 2016
 
Description CB7 
Organisation University of California, San Diego (UCSD)
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PI Contribution Calculations on binding affinity between CB7 and guests
Collaborator Contribution Expertise in free energy calculations
Impact A novel method for free energy estimation. Publication in preparation.
Start Year 2014
 
Description CMTP 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Calculations of binding mode and binding affinity for small molecule inhibitors.
Collaborator Contribution Experimental testing of binding mode and binding affinity for small molecule inhibitors.
Impact Results from experimental testing of binding mode and binding affinity for small molecule inhibitors. New company phoremost formed from intellectual property generated.
Start Year 2014
 
Description MRCT - GluR 
Organisation MRC-Technology
Department MRCT Centre for Therapeutics Discovery (CTD)
Country United Kingdom 
Sector Academic/University 
PI Contribution Prediction of water networks at protein surfaces and rationalisation of small molecule SAR for glutamate receptors.
Collaborator Contribution Crystallography. Experimental testing of small molecule inhibitors.
Impact SAR rationalised, but compounds do not show sufficient activity to be taken further.
Start Year 2014
 
Description MRCT - ULK 
Organisation MRC-Technology
Department MRCT Centre for Therapeutics Discovery (CTD)
Country United Kingdom 
Sector Academic/University 
PI Contribution Prediction of water networks at protein surfaces and rationalisation of small molecule SAR for kinase ULK.
Collaborator Contribution Crystallography. Experimental testing of small molecule inhibitors.
Impact Work ongoing
Start Year 2015
 
Description Phoremost PLK1 
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Sector Private 
PI Contribution Consultancy services on binding site identification and SAR rationalisation
Collaborator Contribution Data on PLK1
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Start Year 2016
 
Description SGC 
Organisation University of Oxford
Department Structural Genomics Consortium (SGC)
Country United Kingdom 
Sector Public 
PI Contribution Analysis of bromodomain ligandability
Collaborator Contribution Data and expertise on bromodomains.
Impact Published on bromodomain ligandability in J Phys Cond Matter.
Start Year 2015
 
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Description Solvaware analyses water around biomolecules 
Type Of Technology Software 
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Company Name INTEGRATED BIOMEDICAL SOLUTIONS LIMITED 
Description Biomedical consultancy 
Year Established 2017 
Impact Consultancy on cancer drug development