Marie Skłodowska-Curie Action
Innovative Training Networks (ITN)
2016-2020

The objectives of FragNet are to (a) train a cohort of ESRs across FBLD methods and (b) develop individual skills in research into either new methods in FBLD or to apply FBLD to interrogate biological systems.

 

 

Projects

ESR1: 3D Fragments with small aliphatic rings

Host: VU University Amsterdam, The Netherlands
Academic supervisors: Dr. Maikel Wijtmans and prof. dr. Iwan de Esch (VU University Amsterdam)
Researcher: David Hamilton

 

Download the full description of this project: ESR1: 3D Fragments with small aliphatic rings

Synopsis

At present, ‘flat’ heterocyclic aromatic compounds seem to be overrepresented in fragment libraries. It is being debated if more fragments with 3D character (mainly arising from sp3-­‐ hybridised carbon atoms) should populate the fragment libraries, even though these have higher complexity (and therefore have a lower chance of binding to a target).

Objectives
1. Develop of novel chemistries leading to fragments that contain small aliphatic rings.
2. The identification of 3D fragments that bind to protein targets. ESR13. The hit optimisation of selected hit fragments.

Approach
The aim is the development of focused libraries of small aliphatic rings, e.g., cyclobutyl-­‐containing fragments. Towards this end, new chemistries with stereochemical control of the products will be developed. The resulting fragments have a higher complexity and their potential (e.g., hit rate and optimisation potential) will be explored by the Fragnet consortium. Fragment hits will be identified and used to fine-­‐tune the focused libraries and to obtain optimized tool compounds for Fragnet projects.

Qualifications
Applicants must have experience with modern organic synthesis, including heterocyclic chemistry, parallel chemistry and air-­‐sensitive reactions. In addition, candidates must have experience in purification and analyses (1D-­‐NMR, 2D-­‐NMR, LC-­‐MS, HR-­‐MS, IR) of organic compounds. An interest in medicinal chemistry and its biological context is also a requirement.

Key publications
1. Wijtmans et al. MedChemComm. 2010, 1, 39-44.
2. de Kloe et al. Discov Today. 2009, 14, 630-46.




ESR2: Novel 3D fragments

Host: University of York, UK
Academic supervisor : Prof. dr. Peter O’Brien and Prof. dr. Rod Hubbard (University of York)
Researcher: Hanna Francesca Klein


Download the full description of this project: ESR2: Novel 3D fragments

Synopsis
The applicant will join a team working on the design, synthesis and assessment of novel 3D fragments. The focus of the project is on chemical synthesis with opportunities to explore aspects of cheminformatics (for analysing compounds), molecular modelling (how the compounds bind to proteins) and experimental fragment screening.

Objectives
1. Design of 3-D fragment library.
2. Synthesis of selected fragments.

Approach
Most of the compounds in fragment libraries[1, 2] are commercially available small molecules which have been selected by medicinal chemists based on their experience on ease of synthesis and what they have seen before in existing drugs. This means that many fragments are flat heterocycles. This has worked well for many proteins that bind to and recognise metabolites such as ATP, but may not be ideal for other proteins, such as those that bind carbohydrates. There are also analyses which suggest that more 3D compounds have better properties as drugs[3]. One of the major issues with such compounds is they contain multiple stereo-­‐centres which makes synthesis to improve the compounds more challenging. Some of the synthetic chemistry developed at York provides a way to achieve this. This project builds on recent work in the O’Brien laboratory (aided by cheminformatics analysis by the Hubbard group) to design and synthesise novel 3D lead-­‐like compounds[4]. The compounds will be designed based on common features of drug molecules and some of our 3-­‐D fragments are shown below. Principal moments of inertia (PMI) plots, which are a representation of 3-­‐D space, will be used to evaluate the designed compounds and selection criteria will be developed to identify compounds. Selected compounds will then be synthesised.

Qualifications
The skills required are an interest and aptitude for compound synthesis; the amount of time spent outside of the synthetic laboratory (on modelling or experimental screening) will depend on the interests of the successful applicant.
ESR2
Key publications
1. Doak et al. http://dx.doi.org/10.1071/CH13280, 2013.
2. Baurin et al. J Chem Inf Comput Sci, 2004. 44, 2157-66.
3. Lovering et al. J Med Chem, 2009, 52, 6752-6.
4. Luthy et al. Bioorg Med Chem, 2015, 23, 2680-94.


ESR3: Warhead Library of Covalent Fragment Binders

Host: RCNS, Hungary (PhD enrolment at Budapest University of Technology and Economics)
Academic supervisor: Prof. dr. György M. Keserű (RCNS)
Researcher: Aaron Keeley
 

Download the full description of this project: ESR3: Warhead Library of Covalent Fragment Binders

Synopsis
The starting points of FBLD studies are highly curated collections of small, chemically diverse and highly soluble fragments. To increase the diversity of the available fragment libraries, ESR3 will design and synthesise a reactive ‘warhead’ library and establish techniques for screening covalent binders against several FragNet protein targets, including kinases.

Objectives
Designing and creating a compound library of fragment sized molecules with reactive warheads: “warhead library”. 2. Establishing techniques for efficient detection of covalent binders in a screening setup. 3. Screening of “warhead” library and virtual hits identified by ESR9 against various protein targets, e.g., Janus kinases. 4. Extending covalent binders into lead-­‐like compounds.

Approach
By using synthetic organic chemistry, computational chemistry and (structure-­‐based) drug design, a general fragment library for screening of covalent ligands will be created. The identification of covalent inhibitors for therapeutically relevant proteins, including Janus kinases, will be explored.

Qualifications
Preparative organic chemistry or theoretical organic chemistry or chemical biology knowledge and lab experience, analytical or bioanalytical background will be beneficial.

Key publications
1. Jöst et al. J. Med. Chem. 2014, 57, 7590-7599
2. Mark et al. J. Med. Chem. 2014, 57, 10072-10079
3. Baskin et al. PLoS ONE 2014, 9(8), e105568.


ESR4: Development of FBLD techniques for Intrinsically Disordered Proteins

Host: Vernalis Research, UK (PhD enrolment at University of York)
Industrial supervisor: Dr Ben Davis (Vernalis Research)
Researcher: Darius Vagrys

 

Download the full description of this project: ESR4: Development of FBLD techniques for Intrinsically Disordered Proteins


Synopsis
FBLD technologies are continuously being improved to capture new opportunities. ESR4 will explore Intrinsically Disordered Proteins (IDPs) and Intrinsically Disordered Regions (IDRs). The significance of these proteins has recently become apparent. This project will begin to evaluate the possibility of using FBLD to develop small molecule ligands that bind to IDPs and IDRs, and modulate their folding and function.

Objectives
1. Evaluate literature studies of ligands binding to intrinsically disordered proteins (IDPs).
2. Identify suitable IDP test system(s) with tractable expression, purification, stability and behaviour in aqueous solution.
3. Evaluate and develop fragment based screening (FBS) methods to identify fragments which bind to the IDP.
4. Validate and evolve initial fragments to show enhanced potency and characterise response of IDP to these ligands.


Approach
A number of IDP-­‐ligand interactions have been identified in the literature, and assessment of these will provide both a key initial dataset and a valuable training in the biophysical techniques and approaches used to study protein-­‐ligand interactions. Evaluation of the suitability of one or more IDPs for FBLD approaches will also provide a robust dataset, since any outcome will be of interest. Once the experimental methodology has been tested on the literature IDP systems, they will applied against one or more tractable IDP or IDR systems, identified either from the literature or through collaborations (for example, with research groups at the University of York who are investigating the structural biology of disease-­‐related IDPs). The experimental methodology will then be extended to screen low affinity fragments for binding to this tractable IDP system, and to characterise the structural and kinetic basis for observed fragment: IDP interactions. Fragments which are determined as validated ligands for the IDP will then be explored through well-­‐described FBLD evolution strategies, such as near neighbour analysis and template morphing, in order to enhance the affinity of the ligand: IDP interaction and if possible to characterise the response of the IDP to ligand binding


Qualifications
An MSc degree in Chemistry, Biochemistry, Biophysics or Molecular Life Sciences is required. Expertise in protein expression and/or protein biophysics is required, along with a keen interest in the protein folding and molecular interactions. The ability to work independently as part of a small team is essential, along with strong communication and interpersonal skills. Previous experience of NMR would be an advantage.


Key publications
1. Tompa et al. 2015 Curr. Opin. Struct. Biol. 35, 49–59.
2. Follis et al. 2008 Chem. Biol. 15, 1149–55.
3. Krishnan et al. 2014 Nat. Chem. Biol. 10, 558-66.


ESR5: Biophysics Based FBLD

Host: ZoBio BV, The Netherlands (PhD enrolment at VU University Amsterdam)
Industrial supervisor: Dr. Gregg Siegal (Zobio)
Researcher: Sébastien Keiffer

 

Download the full description of this project: ESR5: Biophysics Based FBLD


Synopsis
FBLD technologies are continuously being improved to capture new opportunities. This project will investigate emerging antimicrobial targets with state-­‐of-­‐the-­‐art biophysical screening technologies.

Objectives
Use NMR and SPR to screen a fragment library for validated hits against the target protein. 2. Develop NMR structural biology approaches to enable structure based drug design to elaborate hits to potent lead-­‐like molecules. 3. Collaborate with the medicinal chemistry group of Prof. Iwan de Esch to design, synthesize and test elaborated hits.

Approach
This project will seek to develop inhibitors of critical bacterial and/or viral enzymes. In order to do so we will first concentrate on expressing the target in E. coli in a form that is suitable for biophysical and structural biological work. The recombinant protein will be used to screen for ligands specific for the target using ZoBio’s proprietary, NMR-­‐based TINS technology and SPR. The structure of validated hits from this effort bound to the target will be elucidated using protein observed NMR methods. Collaboration with other Fragnet members will bring the possibility to use X-­‐ray crystallography as well. The structural information will be used to design compounds with better potency and ligand efficiency in collaboration with the medicinal chemistry group of Prof. Iwan de Esch. We expect to develop novel compounds that have biological activity in anti-­‐bacterial or anti-­‐viral assays.

Qualifications
A strong bachelors background in chemistry and physical chemistry is important. The successful applicant will have demonstrated some ability to recombinantly express and purify proteins. Any previous experience with NMR, either theoretical or practical, would be a help.

Key publications:
1. van Linden et al. Eur. J. Med. Chem. 2012, 47, 493-500.
2. Vanwetswinkel et al. Chem. Biol. 2005, 12, 207-216.
3. Shah et al. J. Med. Chem. 2012, 55, 23, 10786-10790.


ESR6: FBLD experimental methods

Host: Beactica AB, Sweden (PhD enrolment at Uppsala University)
Industrial supervisor: Prof Helena Danielson (Beactica, Uppsala University)
Researcher: Edward Fitzgerald

 

Download the full description of this project: ESR6: FBLD experimental methods

Synopsis
FBLD technologies are continuously being improved to capture new opportunities. This project will study the use of biosensor-­‐based technologies to study ligand-­‐protein binding events.

Objectives
Develop biosensor-­‐based assays for epigenetic target proteins interacting with histones. 2. Screen proprietary FragNet fragment libraries against selected target proteins. 3. Characterize fragment hits using same biosensor-­‐based methods and orthogonal assays. 4. Use experimental data in computer-­‐assisted drug design. 5. Optimise fragment hits.

Approach
New biosensor instruments and methods will be used for development of highly sensitive and informative assays suitable for epigenetic targets that interact with and modify histone proteins. The methods will address the challenges associated with detection of weakly interacting small molecules (fragments) and will be focused on distinguishing ligands with a functional effect from binders that simply interact with the protein. The assays will be designed for direct or indirect detection of fragments that can directly block interactions with the protein substrate/binding partner or that have enough binding energy to induce the required conformational changes for allosteric inhibition of protein-­‐protein interactions. Biophysical methods will be developed for identifying ligand binding sites, i.e., binding to the protein-­‐protein interaction surface (corresponding to the active site for non-­‐enzyme targets) or an allosteric site. Computational studies of hits will be performed as a complement to experimental studies, with a focus on identifying potential binding sites, binding modes and interaction features of weakly interacting ligands. The design of any new ligands can be supported by computer-­‐aided drug design studies and synthesis will be performed in collaboration with other ESRs.

Qualifications
Required diploma: MSc degree in Biochemistry, Biophysics or related Molecular Life Science degree. Required expertise: Experience in biochemical and/or biophysical characterization of proteins. The candidate has a strong background in biochemistry or biophysics, and has experience in variety of methods for producing proteins and characterizing their structural and functional properties. Recommended expertise: Use of advanced biophysical instruments and development of new biochemical and biophysical assays. An interest in computer-­‐aided drug design and mathematical modelling and statistical analysis of biochemical data would be an advantage. The candidate needs to be able to discuss and develop methods in collaboration with other ESRs.

Key publications
1. Winquist et al. Biochemistry, 2013, 52, 613-626.
2. Gossas et al. Med. Chem. Commun, 2013, 4, 432 – 442
3. Seeger et al . Journal of Molecular recognition 2012, 25, 495–503.
4. Geitmann et al. J. Med. Chem. 2011, 54, 699-708.
5. Elinder et al. J. of Biomolecular Screening, 2011, 16, 15-25.


ESR7: Understanding PDE binding kinetics

Host: VU University Amsterdam, The Netherlands
Academic supervisors: Dr. Chris de Graaf and prof. dr. Iwan de Esch (VU University Amsterdam)
Researcher: Pierre Boronat

 

Download the full description of this project: ESR7: Understanding PDE binding kinetics


Synopsis
This project will investigate of binding kinetic while growing hit fragments, building on interesting data that has already been generated for Trypanosoma brucei Tbr-PDE ligands. The project will combine design, synthesis and molecular dynamics studies to unravel the molecular features of structure-kinetics relationships.

Objectives
1. Use SPR biosensors to measure the differences in binding kinetics of ligands for human hPDE4 and parasite TbrPDE proteins.
2. Perform Random Acceleration Molecular Dynamics (RAMD) studies to determine ligand access and egress mechanisms and factors determining the kinetics of ligand binding to PDEs.
3. Guide fragment hit growing to develop optimised compounds with well-­‐defined kinetic selectivity profiles.


Approach
Trypanosoma brucei (Tbr) is the causative parasite of human African trypanosomiasis (HAT), also known asESR8African sleeping sickness, a disease that has been grossly neglected as it is only a problem in the poorest areas of Africa. Tbr-­‐PDE enzymes are validated drug targets to treat this illness. These Fragnet studies will lead to a better understanding of kinetic binding properties of Tbr-­‐ PDE ligands. This molecular understanding can be used to achieve kinetic selectivity and thereby create safe and efficient drugs for this neglected disease.

Qualifications
AApplicants must have a background in molecular modelling (including molecular dynamics studies). Experience with organic synthesis or SPR biosensor instruments would be an advantage. The project can be fine-­‐tuned according to the background and interests of the successful candidate.

Key publications
1. Jansen et al. J. Med. Chem. 2013, 56, 2087-2096.
2. Orrling et al. Discov Today. 2012, 55, 8745-8756.


ESR8: Virtual Screening of Fragment Libraries of Covalent Binders

Host: RCNS, Hungary (PhD enrolment at Budapest University of Technology and Economics)
Academic supervisor: Prof. dr. György M. Keserű (RCNS)
Researcher: Andrea Scarpino

Download the full description of this project: ESR8: Virtual Screening of Fragment Libraries of Covalent Binders

Synopsis
Computer-aided drug design (CADD) approaches are able to generate accurate molecular models that integrate available structural data with biochemical and biophysical screening data. In this project, we will develop computational chemistry protocols for modelling covalent protein binders and fragment hit evolution.

Objectives
1.Designing a docking and scoring scheme for fragment sized covalent binders. These binding results will be complemented with reaction kinetic data. 2. Designing a computational protocol to extend the covalent fragments to covalent lead like compounds.
3. Virtual screening of commercially available reactive fragments against various proteins including Janus kinases.
4. Extending covalent binders that are identified by ESR3 and confirmed by ESR8 to lead like compounds

Approach
In this project, computational chemistry, molecular modelling, drug design and experimental technics to observe and quantify covalent binders will be combined. These studies will lead to computational methods to identify fragment sized covalent binders. It will also establish computational methods to extend covalent fragments to lead like compounds, e.g., for the identification of inhibitors of FragNet targets, including Janus Kinases (see ESR9).

Qualifications
Applicants must have experience with computational chemistry with a focus on molecular modelling. Familiarity with drug discovery concepts will be an advantage.

Key publications
1. Singh et al. Nature. Rev. Drug Discov. 2011, 10, 307
2. Allen et al. Med. Chem. Commun. 2014, 5, 180.
3. Mah et al. Bioor. Med. Chem. Lett. 2014, 24, 33.


Sébastien Keiffer

ESR9: Fragment evolution platform - chemical navigation

Host: University of Barcelona, Spain
Academic supervisor: Prof. Xavier Barril (University of Barcelona)
Researcher: Moira Rachman


Download the full description of this project:
ESR9: Fragment evolution platform - chemical navigation


Synopsis
Computer-­‐aided drug design (CADD) approaches are able to generate accurate molecular models that integrate available structural data with biochemical and biophysical data. In this project, a computational platform will be established that will help to guide efficient fragment hit evolution.

Objectives
Assemble the necessary cheminformatic infrastructure to generate, store and navigate chemical collections. Docking software will be an integral part of the system in order to exploit structural information, when available. 2. Identify chemical transformations in published fragment evolution programmes, assessing frequency and potency gain. 3. Create an algorithm capable of identifying an optimal list of evolved fragments for testing, given a fragment hit and optional additional information (e.g. list of compounds tested, structural information). 4. Use the platform in prospective FBDD projects, in collaboration with other ESRs.

ApproachESR9
Starting from existing software and computational methods developed in our lab, the ESR will develop a computational platform capable of suggesting an optimal set of molecules to test experimentally. The platform will accept as input a list of active and inactive fragments and, optionally, three-­‐dimensional structures of the target. The ESR will generate robust and adaptable pipelines, combining computational packages in the fields of statistics, chemoinformatics, computational chemistry and others. This work will be carried out in close collaboration with the rest of the FRAGNET consortium to ensure that the final tool offers a practical solution in the majority of fragment-­‐based scenarios. The ESR will also provide training to early adopters and apply the software to existing FBLD projects within FRAGNET.

Qualifications
Required diploma: MSc Bioinformatics or related degree and a background in chemistry, mathematics, pharmaceutical sciences or molecular life sciences. Required expertise: Strong programming and scripting skills. Experience with molecular modelling, chemoinformatics tools, databases, statistical analysis and web interfaces. Recommended expertise: Synthetic chemistry, structural biology, biophysical methods and analysis of screening data would be an advantage. Experience with network analysis or machine learning methods would also be highly valued. An interest in computer-­‐aided drug design and strong interpersonal skills are essential to establish fruitful collaborations within the consortium.

Key publications
1. Radusky et al. Database (Oxford). 2014, 2014(0), bau035.
2. Ruiz-Carmona et al.PLOS Computational Biology 2014, 10(4):e1003571
3. Schmidtke et al. Bioinformatics, 2011, 27(23), 3276-3285
4. Schmidtke et al. J. Med. Chem. 2010, 53(15), 5858–5867


ESR10: Fragment evolution platform – molecular simulations

Host: University of Barcelona, Spain
Academic supervisor: Prof. Xavier Barril (University of Barcelona)
Researcher: Maciej Majewski

Download the full description of this project: ESR10: Fragment evolution platform – molecular simulations

Synopsis
For efficient hit optimisation, a thorough understanding of fragment-­‐protein binding is necessary. Computer‐aided drug design (CADD) approaches are able to generate accurate molecular models that integrate available structural data with biochemical and biophysical screening data. In this project, a computational platform will be established that will help to study the binding kinetics of fragment‐protein and ligand‐protein binding.

Objectives
1.Development of fast simulation-­‐based methods for fragment screening and evolution.
2. Comparison of unbiased (association) and biased (dissociation) MD simulations for binding mode prediction and virtual fragment screening.
3. Integration of simulation-­‐based methods within the fragment evolution platform.
4. Prospective application of simulation-­‐based methods. 


Approach
The ESR will initially apply computational methods developed in the group (MDmix, Dynamic Undocking) to existing projects, andESR10 then proceed to implement advanced sampling molecular dynamics methods that extend the applicability of our current tools. The specific problems of fragment binding mode identification, virtual fragment screening and fragment evolution will be examined with several alternative approaches that will be systematically compared. Optimized protocols will be developed for specific problems and integrated within a fragment evolution platform that will be developed in parallel. The methods will be evaluated prospectively in collaboration with other ESRs.

Qualifications
Required diploma: MSc Computational Chemistry, Bioinformatics or similar degree and a background in chemistry, physics, pharmaceutical sciences or molecular life sciences. Required expertise: Experience in molecular simulations of biomolecular systems and a solid knowledge of statistical thermodynamics and biophysical methods. Recommended expertise: structural biology, molecular biology or synthetic chemistry would be an advantage. Experience with NMR, ITC, SPR would be highly valued. An interest in computer-­‐aided drug design and strong interpersonal skills are essential to establish fruitful collaborations within the consortium.

Key publications
1. Alvarez-Garcia et al. J. Med. Chem. 2014, 57, 8530–8539.
2. Alvarez-Garcia et al. J. Chem. Theory Comput. 2014, 10, 2608–2614.
3. Schmidtke et al. J. Am. Chem. Soc. 2011, 133, 18903-18910.
4. Seco et al. J. Med. Chem. 2009, 52, 2363-2371.


ESR11: Fragment-based approaches to identify novel PPI inhibitors

Host: VU University Amsterdam, The Netherlands
Academic supervisors: Dr. Jacqueline van Muijlwijk and prof. dr. Iwan de Esch (VU University Amsterdam)
Researcher: Lorena Zara
 

Download the full description of this project: ESR11: Fragment-based approaches to identify novel PPI inhibitors

Synopsis
FBLD technologies are continuously being improved to capture new opportunities. This project will interrogate emerging antimicrobial targets by fragment hit identification and fragment growing, linking and merging approaches.

Objectives
Design and synthesise compounds for antimicrobial protein targets, starting from existing hits of fragment library screening. 2. Perform ITC and SPR screening and develop ligand binding models. 3. Develop accurate ligand-­‐protein binding models using X-­‐ray, 15N-­‐NMR data and CADD data (in collaboration with ESR5).

ApproachESR11
In a joined effort with Zobio, VU University Amsterdam is exploring a couple of antimicrobial targets using FBLD approaches. In this project we will design and synthesize optimized hit fragments and drug-­‐like compounds. Computer-­‐aided drug design will be combined with the synthesis of series of compounds that interrogate the protein targets. Using the biochemical and biophysical screening data that will be generated (amongst others by ESR5), structure-­‐activity relationships, structure-­‐kinetics relationships and structure-­‐thermodynamics relationships will be explored and used to optimize the hit fragments.

Qualifications
Applicants must have a background in medicinal chemistry and have ample experience in computer-­‐aided drug design and the synthesis and characterisation of novel ligands. We are looking for an enthusiastic team player that is eager to collaborate with others.

Key publications
1. Edink et al. J.Am. Chem. Soc. 2011, 133, 5363-5371.
2. De Kloe  J. Med. Chem. 2010, 53, 7192-7201.


ESR12: Covalent fragments to activate industrial enzymes

Host: University of York, UK
Academic supervisors: Prof. dr. Peter O’Brien and Prof. dr. Rod Hubbard (University of York)
Researcher: Eleni Makraki

 

Download the full description of this project: ESR12: Covalent fragments to activate industrial enzymes



Synopsis
As a novel fragment-based application, this project will identify fragments to activate enzymes that are used for chemical conversions in industry and covalently attach the fragments to the enzymes and optimise hit fragments that increase enzyme activity. The student will join a team working on fragment-based methods for activating industrial enzymes.

Objectives
1. To identify fragments that activate industrial enzymes such as amylase and cellulase.
2. To characterise the kinetics, mechanism of action, substrate and product profiles of enzymes activated by fragments.
3. To design covalent strategies to attach the fragments to the enzymes for biotechnology applications.

Approach
The York laboratory has recently demonstrated that small fragments can increase the activity of an enzyme[1]. A project is beginning during 2016 to extend this work in two directions. The first is to identify activators for other enzymes, such as cellulase and glycosidases which are used industrially for pulp processing and bioenergy production. The second is to explore synthetic methods for covalently attaching these activating fragments to the enzyme. This should increase the activity but crucially mean that the compounds are not lost in the industrial process.

Qualifications
The details of the project for the student will be decided during the summer of 2016 but will also be tuned to the interests and aptitude of the student. If the primary interest is synthetic chemistry, then there are a number of different attachment strategies to be explored, including some new ideas in this area of bio-orthogonal chemistry. If the primary interest is fragment-based discovery and enzyme activation, then there are a number of industrial enzymes that are being prepared for study.

Key publications

1. Darby et al. Angewandte Chemie, 2014, 53, 13419-13423.


ESR13: Fragment-based assessment of new antibiotic targets

Host: University of York, UK
Academic supervisors: Prof. dr. Peter O'Brien and Prof. dr. Rod Hubbard (University of York)
Researcher: Bas Lamoree

 

Download the full description of this project: ESR13: Fragment-based assessment of new antibiotic targets

Synopsis
Fragment-­‐based approaches will interrogate protein targets and identify potential drug targets.

Objectives
1. To use computational screening methods to characterise a set of proteins from the bacterial DNA replication machinery. 2. To over-­‐express, purify and characterise protein for at least two such targets, determining crystal structures. 3. Conduct screening against the targets, identifying and characterising fragment hits. 4. SAR by catalogue and limited chemical synthesis to optimise the fragment hits and assess in bacterial replication assays.

Approach
The student will use the methods of fragment-­based discovery[1] to assess which of the proteins in the bacterial replisome are potential targets for antibiotics. The bacterial replisome consists of some 15 proteins which together replicate DNA within a bacterial cell. The McGlynn group is one of the few in the world that can reconstitute this molecular machine in the test tube. The aim of this project is to use fragment-­‐based methods to assess whether any of the proteins (or the complexes they make) are suitable targets for the development of new classes of antibiotics. The crystal structures for many of the proteins are already available and another laboratory has already identified fragments and

ESR13

 optimised compounds for one of the proteins (the β sliding clamp)[2]. Preliminary screening of the York fragment library is planned for Summer 2016 and the outcomes of these screens will inform the precise direction of the project. There are multiple assays available to characterise the effect of any inhibitory fragments on the functionality of the entire replisome, subcomponents and individual enzymes[3-­5]. The project will focus on fragment hits for a number of different targets, characterise binding using biophysical methods such as NMR, SPR and ITC, determine crystal structures of the fragment-­enzyme complexes and explore preliminary optimisation of the compounds by purchase of similar compounds. In addition, there will be opportunities for computational work centred on identifying potential inhibitor binding sites within individual replisome components using molecular docking calculations.

 

Qualifications
The skills required are an interest in protein structure and function and an aptitude for the methods of characterising biomolecular interactions.

Key publications
1. Hubbard et al. Methods Enzymol, 2011. 493, 509-31.
2. Yin et al. J. Med. Chem. 2014. 57, 2799-806.
3. Gupta et al. J Biol Chem. 2010, 285, 979-87.
4. Gupta et al. Proc Natl Acad Sci U S A, 2013, 110, 7252-7.
5. McGlynn et al. J Mol Biol, 2008, 381, 249-55.


ESR14: Targeting allosteric pockets with FBLD

Host: Novartis Pharma AG (PhD enrolment at VU University Amsterdam)
Industrial supervisors: Dr. Andreas Marzinzik and Dr. Wolfgang Jahnke (Novartis)
Researcher: Lena Münzker


Download the full description of this project:
ESR14: Targeting allosteric pockets with FBLD


Synopsis
In this project, FBLD approaches will be applied in the area of neglected diseases by targeting allosteric binding pockets of farnesyl pyrophosphate synthase (FPPS) to generate ligands that kill the parasite Trypanasoma brucei.

Objectives
Collaborate with AEGIS ITN student to set up fragment screening and characterization (NMR, SPR, X-­‐ray crystallography) for parasite Trypanosoma brucei farnesyl pyrophosphate synthase (FPPS) 2. Design improved ligands by molecular modelling 3. Optimise fragment hits for allosteric binding pocket, with respect to potency, permeability, selectivity and pharmacokinetic properties

Approach
Trypanosoma brucei (Tbr) is the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness, a disease that has been largely neglected in the Western world for a long time. The World Health Organization and other neglected diseases organisations such as the DNDi encourage the development of new and effective medication against this disease. It has been shown that bisphosphonate FPPS inhibitors are effective anti-­‐parasite compounds, however the pharmacokinetic properties do not allow the use for this indication. In this project, FBLD will be used to target an allosteric binding pocket and will optimise effective anti-­‐parasite treatments. This position is strongly connected to a PhD position within the AEGIS ITN where protein expression and structural biology will be performed. Both PhD students will closely collaborate with each other and within the ITN. The targets pursued within the ITNs are non-­‐confidential and the research results can be published.

Qualifications
You should have: a master of Science degree in chemistry, biochemistry, physical or life sciences. You need an interest in drug discovery, structural biology and medicinal chemistry. And the ability to work independently as part of a small research team. Also important is are a strong motivation and communication skills


ESR15: Science, Business & Innovation in the pharmaceutical sciences

Host: VU University Amsterdam, The Netherlands
Academic supervisors: Prof. Peter van der Sijde, dr. Iina Hellsten & dr. Jacqueline van Muijlwijk (VU University Amsterdam)
Researcher: Angelo Kenneth Romasanta

Download the full description of this project: ESR15: Science, Business & Innovation in the pharmaceutical sciences

Synopsis
In this project, we will study innovation management in pharmaceutical sciences with a focus on the pharmaceutical (disruptive) innovation in the open innovation landscape which enables academia and SMEs to participate in lead discovery and chemical biology approaches. The ESR will study the absorptive capacity in academia, SMEs and pharma. Furthermore, pharmaceutical innovation management through collaboration networks between university, industry and government (triple helix) will be considered, using FBLD as a case study and secondly via mapping publication- and patent data to identify relationships and dependencies between start-ups, SMEs and big pharma in innovation dissemination.

 

Objectives
1. Study the disruptive innovation aspects of FBLD in respect to older technologies.
2. Using FBLD as case study, describe the absorptive capacity of SMEs, big pharma and academic institutes (EU, USA).
3. Study FBLD aspects in triple helix projects and describe best practice with respect to innovation and IP management.

Approach
These studies will reveal the differences in innovation management in different settings of pharmaceutical sciences (start-­‐up, small company, large company) and how knowledge disseminates through the networks. This will also help all FragNet ESRs to better position and present their inventions (disseminative capacity). The results of the ESR15 will be published as scientific articles, and a PhD Dissertation.

Qualifications
We are looking for a PhD candidate with proven affinity in combining sciences and social sciences, for example through science and technology studies approaches, in particular within medical and/or pharmaceutical innovations. The successful candidate is interested in bridging the (exact) sciences and the social sciences, and holds, preferably, and (BSc or MSc) degree in (medicinal) chemistry, chemical biology or pharmaceutical sciences, and a (BSc or MSc) degree or attended (relevant) courses in social sciences.

Key publications
1. Schumacher A., German PG., Trill H., Gassmann O. (2013). Models for open innovation in the pharmaceutical industry. Drug Discovery Today, 18: 1133-7.
2. Leydesdorff, L. & Ahrweiler, P. (2014) In Search of a Network Theory of Innovations: Relations, Positions, and Perspectives, Journal of the American Society for Information Science and Technology 65(11): () 2359-2374
3. Freitas, I. M. B., Marques, R. A., & e Silva, E. M. D. P. (2013). University–industry collaboration and innovation in emergent and mature industries in new industrialized countries. Research Policy, 42(2): 443-453.


 

 

PERT Chart  relations between WPs-Workshops-ESRs

Lijndik