Europe: 14 MSCA PhD Positions in Drug Discovery

14 Early Stage Researcher (ESR) positions are available within the EU-funded Marie Skłodowska Curie Innovative Training Network on Allostery in Drug Discovery (ALLODD), in the following highly reputed organisations:

BIOMEDICAL RESEARCH FOUNDATION ACADEMY OF ATHENS (BRFAA), Greece

UNIVERSITY OF VIENNA (UNIVIE), Austria

UNIVERSITAT DE BARCELONA (UB), Spain

FORSCHUNGSZENTRUM JULICH GMBH (FZJ), Germany

CHARITE – UNIVERSITAETSMEDIZIN BERLIN (Charité), Germany

TERMESZETTUDOMANYI KUTATOKOZPONT/Research Center for Natural Sciences (RCNS), Hungary

FORSCHUNGSVERBUND BERLIN EV (FMP), Germany

KAROLINSKA INSTITUTET (KI), Sweden

HEPTARES THERAPEUTICS LIMITED (Heptares), United Kingdom

UNIVERSITE DE STRASBOURG (Unistra), France

MERCK HEALTHCARE KGAA (Merck), Germany

JANSSEN PHARMACEUTICA NV (Janssen), Belgium

UNIVERSITY OF URBINO (UNIURB), Italy

PROJECT DESCRIPTION

The ALLODD project is a collaboration between 13 academic and industrial organizations with 14 PhD students in total. The aim of ALLODD is to train a new generation of scientists to exploit the concept of allostery in drug design, putting together a whole array of technologies to identify and characterize allosteric modulators of protein function that will be applied to therapeutically relevant systems.

Most current drugs are designed to bind directly to the primary active sites (also known as orthosteric sites) of their biological targets. Allosteric modulators offer a powerful yet underexploited therapeutic approach. They can elicit a richer variety of biological responses and, since they target less conserved binding sites, higher selectivity and less adverse effects may be obtained. ALLODD aims to train a new generation of scientists in exploiting the concept of allostery in drug design, putting together a whole array of technologies to identify and characterize allosteric modulators of protein function that will be applied to therapeutically relevant systems. Our approach is based on a combination of experimental and simulation techniques, including fragment Screening with structural characterization (X-ray, NMR, H/D exchange), proteomics (MS/MS), ITC, DNA encoding libraries, Virtual Screening, Molecular Dynamics simulations-based methods, Synthetic Chemistry, and in vitro and cellular assays for the verification of results. It should also be noted that allosteric targeting need not be achieved solely through the design of synthetic small molecules but also can also be reached via conformationally specific allosteric antibodies, which represents an important field of future research. There are already clear examples of monoclonal antibodies that allosterically target ion channels, GPCRs, and RTKs, as well as cytokine and integrin receptors.

JOB OFFER DETAILS

We provide a structured 3-year cutting-edge Research/PhD training programme in and beyond the fields of physical chemistry of biological systems, theoretical and computational chemistry, biological chemistry, biochemistry, targeted drug delivery/discovery and medicinal chemistry.

The earliest starting date will be 1 November 2021 The latest will be 1 September 2023.

We are looking for highly motivated and talented researchers at the beginning of their carrier that are interested in the aforementioned scientific fields based on the specific requirements noted below in each position. Excellent command of spoken and written English, communication skills as well as team spirit are essential.

We are offering a competitive, interdisciplinary environment with a track record of intense mutual collaboration. In addition to the individual training-through-research our programme includes further elements such as workshops, summer schools, internships and secondments to the partners’ laboratories.

The following eligibility rules apply for participation in a Marie Skłodowska Curie Innovative Training Network:

Applicants must be in the first 4 years after obtaining their Master´s degree and/or Bachelor’s degree and must not have resided or carried out their main activity (work, studies, etc.) in the host country for more than 12 months in the 3 years immediately before the recruitment date. In addition, local regulations of the host countries may apply. The salary is based on standard living, mobility and family allowances which are adapted to the respective country of recruitment.

For specific requirements for each ESR position, please read the Specific Requirement(s) section for the respective ESR position.

AVAILABLE POSITIONS

ESR 1: Development of a computational methodology to detect allosteric pathways in proteins and application in drug discovery

Host Organisation: BRFAA

Scientist-in-Charge: Dr. Zoe Cournia

contact email: Applicants should apply by email to zcournia@bioacademy.gr indicating Reference: ALLODD_ESR1.

Objectives: Characterize protein conformational ensembles (from NMR or clustering MD trajectories) based on their aminoacid physico-chemical properties, produce features from these properties and select the most discriminant using Linear Discriminant Analysis or Principal Component Analysis, train, test, and validate multiple Machine Learning, Deep Learning, and Ensemble Learning algorithms on proteins with known allosteric pathways in order to classify aminoacids that contribute to protein allosteric pathways. Assess the viability of binding sites as allosteric pockets using normal mode analysis or elastic network models. Perform computer-aided drug design in the identified pockets.

Expected Results: Creation of a predictive platform for identifying allosteric networks in proteins; assessment and improvement of current methods to assess the implication of binding pockets in large scale protein motions. Delivery of putative allosteric modulators by computer-aided drug design.

Planned Secondement(s):

• Host1: Charité, length: 3 months, purpose: training in X-ray crystallography

• Host2: KI, length: 3 months, purpose: training in HDX experiments

• Host3: Janssen, length: 2 months, purpose: training in computer-aided drug design

Enrolment in Doctoral degree(s): The ESR will have the possibility to be enrolled in any European University upon mutual agreement.

Specific Requirements: Experience with biomolecular simulations, computational chemistry and/or programming skills are desirable. Bachelor's or Master's degree in Chemistry, Physics, Pharmacy, Biochemistry, Engineering, Computer Science, or related field is required.

Excellent oral and writing skills are required.

ESR2 : Biophysical characterization of allosteric interactions using NMR spectroscopy

Host Organisation: UNIVIE (www.univie.ac.at)

Scientist-in-Charge: Dr. Christoph Rademacher

contact email: Applicants should apply either through the portal of the university or by email to jobcenter@univie.ac.at and use Reference number: 12284

Objectives: Most drugs on the market are designed to bind directly to primary active sites (also known as orthosteric sites) of their biological targets. Allosteric modulators offer important advantages over orthosteric ones: they can be more selective because allosteric sites are less conserved, they can change protein levels or localization within the cell, change subtle aspects of protein function (e.g. form or conformation of the quaternary structure) and are unique in their ability to provide enzymatic activation. Furthermore, allosteric drugs can be used synergistically with orthosteric ligands, an approach that has been successfully used to prevent emergence of resistance in cancer therapy. Allostery may also be the key to drug proteins that have been considered undruggable due to the absence of a known active site, such as KRAS. The Rademacher lab investigates the identification and development allosteric drugs using C-type lectin receptors as targets applying biophysical methods such as NMR and SPR. Involvement in drug discovery teaching is optional.

1) Identification and characterization of potential allosteric sites and allosteric modulators from biophysical screening.

2) Application of ligand-based NMR methods (STD, waterLOGSY, 19F NMR, CPMG-filtering) for screening and druggability assessment of target proteins.

3) Binding site identification and validation using protein NMR methods (HSQC, TROSY) using either 15N labeled protein or incorporation of fluorinated amino acids (W/Y/F) into larger receptor complexes.

4) Identification of allosteric signal transmission pathways in proteins using CHESPA and related methods as well as incorporation site specific labels ( 19F-labeled amino acids e.g.W/Y/F).

Expected Results: 1) Druggability assessment and allosteric site identification from fragment-based screening using ligand-based NMR. 2)Verification and characterization of allosteric sites using protein NMR techniques.

Planned Secondement(s):

• Host1: UB, timing M10, length: 2 months, purpose: training in computer-aided drug design,

• Host2: Merck, timing: M18, length: 3 months, purpose: training in cell-based assays, Host3: KI, timing M30: length: 3 months, purpose: training in HDX experiments

Enrolment in Doctoral degree(s): No.

Specific Requirements:

1) MSc degree, excellent knowledge in Biochemistry and Structural Biology.

2) Very good knowledge of written and spoken English.

Desirable but not Required Skills: Knowledge in NMR spectroscopy as well as the expression and purification of lectins from E. coli inclusion bodies.

Application documents: Letter of motivation – academic curriculum vitae (incl. publication list) – contact details of people who could provide a letter of reference.

ESR3 : Allosteric modulators of Fbw7 E3 ligase

Host Organisation: UB

Scientist-in-Charge: Prof. Xavier Barril (www.ub.edu/bl)

contact email: Applicants should apply by email to xbarril@ub.edu indicating Reference: ALLODD_ESR3.

Objectives: 1) Detect cryptic pockets in Fbw7. 2) Determine binding site and binding mode of existing Fbw7 ligands. 3) Improve potency and modulate allosteric response of ligands.

Expected Results: Structural, dynamic and druggability characterization of Fbw7 allosteric pockets. Structural characterization of existing Fbw7 ligands and fragments. Optimization of allosteric ligands as chemical probes for this tumour suppressor. Understand wider implications for other WD40 repeat domain proteins, as this is one of the most common protein-protein interaction domains.

Planned Secondement(s):

• Host1: KI, length: 3 months, purpose: application of HDX experiments on Fbw7,

• Host2: RCNS, length: 3 months, purpose: synthetize reactive analogues for confirmation of binding mode.

• Host3: Novo Nordisk, length 2 months, purpose: training in modelling of peptides as allosteric modulators

Enrolment in Doctoral degree(s): The ESR will be enrolled in the Ph.D. school at the University of Barcelona (UB).

Specific Requirements: MSc Computational Chemistry, Bioinformatics or similar, and a background (BSc) in chemistry, physics, pharmaceutical sciences or molecular life sciences. Excellent oral and writing skills.

Desirable but not Required Skills: Experience/interest in biophysics, structural biology and/or synthetic chemistry. Programming and scripting skills. Experience in the simulation of biomolecular systems. Good interpersonal skills will facilitate fruitful collaborations within the consortium.

ESR4 : Excitation energy transfer applied to drug design

Host Organisation: UB

Scientist-in-Charge: Prof. Carles Curutchet

contact email: Applicants should apply by email to carles.curutchet@ub.edu indicating Reference: ALLODD_ESR4.

Objectives: The Förster resonance energy transfer (FRET) technique is an important tool in structural biology, due to its ability to monitor and measure distances in biological systems. The Curutchet lab investigates the spectroscopy and FRET properties of biosystems using multiscale computational models. In this context, multiscale strategies combining Molecular Dynamics simulations and efficient models to estimate FRET couplings will be used to help in the structural characterization of allosteric binding sites/modes and allosteric conformational transitions, including the following objectives: 1) Develop a tool to generate FRET observables from MDs; 2) Determine the impact of flexible/rigid linkers on FRET; 3) Assess the ability of FRET simulations to characterize binding sites and binding modes.

Expected Results: 1) Release a computational toolbox to generate FRET data from MDs; 2) Quantify the gain in resolution provided by FRET studies based on rigid linkers; 3) Determine the binding sites of different ligands for drug discovery targets.

Planned Secondement(s):

• Host1: GTx, length: 2 months, purpose: Application of the developed computational tools to assess the binding site of allosteric pharmacological chaperones developed at GTx;

• Host2: Heptares, length: 3 months, purpose: application to undisclosed allosteric target + training in computer-aided drug design.

• Host3: UNIVIE, length: 3 months, purpose: training in NMR for allostery.

Enrolment in Doctoral degree(s): The ESR will be enrolled in the Ph.D. school at the University of Barcelona (UB).

Specific Requirements:

1) Bachelor's or Master's degree in Chemistry, Physics, Pharmacy, Biochemistry, or related field.

2) Excellent English oral and writing skills.

3) Experience in computational chemistry is desirable.

4) Knowledge in programming with Python or other languages is desirable.

ESR5 : Allosteric drugs development for receptor mosaics

Host Organisation: FJZ

Scientist-in-Charge: Prof. Giulia Rossetti

contact email: Applicants should apply by email to g.rossetti@fz-juelich.de indicating Reference: ALLODD_ESR5.

Objectives: 1) understand receptor mosaics (RMs) allosteric-driven signaling mechanism at the molecular level due to receptor associations and allosteric RM interplay; 2) develop new multi-target allosteric ligands tailored to pharmacologically relevant RMs.

Expected Results: 1) Computational multiscale workflows to determine RMs allosteric interplay; 2) development of protocols to deliver allosteric drug candidates tailored for modulating the pharmacological response of RMs.

Planned Secondement(s):

• Host1: BRFAA, length: 2 months, purpose: training in machine learning techniques for allostery,

• Host2: Unistra, length: 2 months, purpose: training in neurotransmitter receptors modelling.

• Host3: UCB, length 3 months, purpose: training in allosteric drug design.

Enrolment in Doctoral degree(s): The ESR will be enrolled in the Ph.D. school at the RWTH Aachen.

ESR6 : Structural elucidation of allosteric mechanisms in G-protein coupled receptors or other membrane proteins by structural biology methods

Host Organisation: Charité

Scientist-in-Charge: Dr. Patrick Scheerer

contact email: Applicants should apply by email to patrick.scheerer@charite.de indicating Reference: ALLODD_ESR6.

Objectives: 1) Large-scale expression and purification of specific GPCRs (Rhodopsin, MC4R, un-named specific GPCR targets) or other membrane proteins , 2) Biophysical characterization of allosteric modulator binding to the selected GPCRs targets using Microscale Thermophoresis (MST) or Nano differential scanning fluorimetry (nanoDSF) technologies and Microscale fluorescent thermal stability (CPM) assays or additional cell signaling assays (e.g. nanoBRET). , 3) Structural characterization of the selected receptor-ligand complexes (allosteric ions, modulators, peptides) using protein X-ray crystallography or cryo-EM).

Expected Results: Structural determination and visualization of diverse allosteric ligand binding sites in GPCRs. Elucidation of interrelations between identified binding sites and understanding underlying mechanisms of allosteric effects.

Planned Secondement(s):

• Host1: UNIURB, length: 2 months, purpose Training MD methods to investigate binding kinetics of allosteric modulators,

• Host2: Novo Nordisk, length: 3 months, purpose: training in peptides as allosteric modulators.

• Host3: FZJ, length 2 months, purpose: training in allosteric drug=targeting of GPCRs.

Enrolment in Doctoral degree(s): No.

ESR7 : Design and synthesis of covalent allosteric probes

Host Organisation: RCNS

Scientist-in-Charge: Dr. György Keserű

contact email: Applicants should apply by email to keseru.gyorgy@ttk.hu indicating Reference: ALLODD_ESR7.

Objectives: Develop computational tools to analyse and predict druggable allosteric sites suitable for covalent targeting. Develop workflows for optimizing covalent allosteric probes. Deliver high affinity and specific covalent probes for the identification of allosteric pockets on selected protein targets.

Expected Results: Established methodology to predict druggable allosteric sites and to design covalent allosteric probes. Validated protocol for optimizing high affinity and specific covalent allosteric probes. Covalent allosteric probes for the targets investigated by the network.

Planned Secondement(s):

• Host1: Heptares, length: 2 months, purpose: modelling water networks using WaterFLAP and WaterMAP.

• Host2: UB, length: 2 months, purpose: training in dynamic undocking and MDmix methodologies.

• Host3: FMP, length 3 months, purpose: training in fragment synthesis.

Specific Requirements:

1) MSc degree, excellent knowledge in Synthetic Organic and/or Medicinal Chemistry.

2) Good communication and writing skills in English.

Enrolment in Doctoral degree(s): The ESR will be enrolled in the Ph.D. school at the Budapest University of Technology (BME).

ESR8 : Design and synthesis of allosteric phosphatase inhibitors

Host Organisation: FMP

Scientist-in-Charge: Dr. Marc Nazaré

contact email: Applicants should apply by email to Nazare@fmp-berlin.de indicating Reference: ALLODD_ESR8.

Objectives: 1) Identification and chemical optimization of novel allosteric inhibitors of SHP2 and PTP1B from biochemical screening and by fragment hybridization. 2) Identification of minimal binding fragments by deconstruction of known allosteric ligands for addressing the binding site of SHP2 and PTP1B. 3) Characterization of synergistic effects of dual inhibition of the active site and allosteric site in SHP2 and PTP1B.

Expected Results: 1) Toolbox of allosteric ligands for phosphatase inhibition based on novel chemotypes. 2) Characterization of the energetic contribution 3) Understanding of the interrelationship of synergistic combinations of active site and allosteric inhibitors of SHP2 or PTP1B.

Planned Secondement(s):

• Host1: RCNS, length: 3 months, purpose: training in covalent ligand synthesis.

• Host2: UNIGE, length: 3 months, purpose: training in metadynamics protein simulations.

• Host3: GTx, length 2 months, purpose: training in non-competitive pharmacological chaperones.

Enrolment in Doctoral degree(s): No.

Specific Requirements:

1) MSc degree, excellent knowledge in Synthetic Organic Chemistry and Biochemistry.

2) Very good communication and writing skills in English.

Desirable Skills: Knowledge of in-silico docking and molecular dynamics simulation and NMR spectroscopy.

ESR9 : Identification of target binding sites using HDX MS and off-targets using Proteome Thermo Profiling

Host Organisation: KI

Scientist-in-Charge: Dr. Roman Zubarev

contact email: Applicants should apply by email to roman.zubarev@ki.se indicating Reference: ALLODD_ESR9.

Objectives: A key aspect of the characterization of allosteric sites is their precise localization on the protein target using biophysical methods. In this context, binding-site characterization by differential amide hydrogen/deuterium exchange mass spectrometry (HDX MS) will be used for rapid detection and validation. Although HDX MS has lower spatial resolution (4-8 amino acids) than X-ray crystallography, its speed (≈ 1-2 weeks), low sample consumption (200 nmols) and simplicity (no necessity of protein crystals) makes it an ideal tool for fast binding site confirmation. For each protein, a set of 5 to 10 ligands will be chosen for binding-site characterization. 2) MS methods also provide the key to explore and understand off-target effects (by Proteome Thermo Profiling).

Expected Results: 1) Identification and validation of allosteric sites using HDX MS; 2) Identification of off-targets using Proteome Thermo Profiling; 3) Establishing a target/off-target relationship for allosteric modulators

Planned Secondement(s):

• Host1: UNIVIE, length 3 months, purpose: training in NMR.

• Host2: UCB, length: 3 months, purpose: training in allosteric drug design in an industrial setting,

• Host3: BRFAA, length: 2 months, purpose: training in comparing HDX experiments with MD simulations.

Enrolment in Doctoral degree(s): The ESR will be enrolled in the Ph.D. school at the Karolinska Institutet (KI).

ESR10 : Computer-aided drug discovery of GPCR allosteric modulators

Host Organisation: Heptares

Scientist-in-Charge: Dr. Chris de Graaf

contact email: Chris.DeGraaf@SoseiHeptares.com

Objectives: 1) Develop a structural cheminformatics platform that integrates chemical, biological and structural data on allosteric interactions with GPCRs. 2) Identify structural determinants of allosteric modulation of GPCRs for structure-based ligand design. 3) Develop computer-aided drug discovery methods for virtual screening and structure-based design of allosteric modulators of GPCRs.

Expected Results: The cheminformatics platform integrating chemical, bioactivity, and structural data on allosteric GPCR binding sites will increase our understanding of the structural determinants of GPCR allosteric modulation. Insights in the role of water networks and lipophilic hot spots in allosteric modulation of GPCRs will enable the development of virtual screening and computer-aided drug design approaches to identify and design allosteric modulators of GPCRs.

Planned Secondement(s):

• Host1: RCNS, length: 2 months, purpose: Training FTMap methodologies for the identification of receptor-ligand interaction hotspots in allosteric GPCR binding sites,

• Host2: UB, length: 2 months, purpose: Training dynamic undocking and MDmix methodologies to investigate transient allosteric GPCR binding sites,

• Host3: UNIURB, length: 2 months, purpose: Training MD methods to investigate binding kinetics of allosteric GPCR modulators

Enrolment in Doctoral degree(s): The ESR will have the possibility to join a three-year PhD program at UNIURB starting Autumn 2022, under the supervision of Dr. de Graaf (Heptares) and Prof. Bottegoni (UNIURB).

Specific Requirements:

1) A Master's degree in Chemistry or a related discipline

2) Keen interest in applying computational tools to address complex chemical and biological questions

3) Excellent inter-personal, oral and written communication skills in a collaborative working environment

4) Experience in computational chemistry, cheminformatics, and/or computer-aided drug discovery is desirable

ESR11: Rational design of positive and negative allosteric modulators of pLGICs

Host Organisation: Unistra

Scientist-in-Charge: Prof. Marco Cecchini

contact email: mcecchini@unistra.fr

Objectives: 1) The development of a state-based pharmacology approach for the rational design of PAMs and NAMs in allosteric proteins. 2) The development of an efficient methodologyfor massive rescoring of docking poses by simplified free energy approaches. 3) The discovery of novel PAMs and NAMs of the human glycine receptor α1.

Expected Results: 1) The identification of novel allosteric modulators of the human GlyR α1 to enter the lead optimization stage. 2) The development of a computational platform (ChemFlow) for the efficient evaluation of protein-ligand binding affinities by docking with free energy rescoring on GPU computing.

Planned Secondement(s):

• Host1: FZJ, length: 2 months, purpose: in allosteric pathways for GPCRs,

• Host2: FMP, length: 2 months, purpose: Training in medicinal chemistry approaches to fragment design,

• Host3: Janssen, length: 3 months, purpose: Training in computer-aided drug design and AI methods for allosteric modulator development.

Enrolment in Doctoral degree(s): The ESR will be enrolled in the Ph.D. programm of Unistra.

ESR12 : Identification of new targets from screening using biochemical and cell based assays

Host Organisation: Merck Healthcare KGaA

Scientist-in-Charge: Dr. Lars Toleikis

contact email: lars.toleikis@merckgroup.com

At the Healthcare business of Merck, we design and develop medicines and intelligent devices that provide ongoing care for patients beyond their treatment. This includes new medications to treat conditions such as cancer or multiple sclerosis (MS), but also innovative technologies that make life easier for patients. For example, our injection device and disease monitoring software allow patients with MS to self-inject their medicine and monitor its administration. With cancer, our precise approach uses biomarkers that can match potential treatment to individual patients.

Objectives: 1) Development of biochemical assays to detect allosteric inhibitors from screening. 2) Retrospect analysis of available in-house targets with known allosteric inhibition mechanism. 3) Expanded the methodology to new target classes with unknown allosteric mechanism in the frame work of the consortium for medium to high throughput screening methods.

Expected Results: 1) New biochemical assay platform for the medium to high throughput detection of allosteric inhibitors. 2) Validation of known allosteric inhibitors from biochemical screening. 3) Transfer of methodology to new target classes.

Planned Secondement(s):

• Host1: UB, length 3 months, purpose: training in FRET,

• Host2: BRFAA, length 2 months, purpose: training in allosteric pathway identification.

• Host3: Unistra, length 2 months, purpose: training in neurotransmitter receptors modelling.

Enrolment in Doctoral degree(s): tbd.

Specific Requirements:

1) Master's degree in biochemistry, biotechnology, molecular biology, pharmacology or a related field.

2) Knowledge of protein chemistry.

3) Experience with biochemical assay systems.

4) Experience with cellular assay systems characterizing biological function.

5) Strong oral and written communication skills.

6) Knowledge of antibody biology is a plus.

ESR13 : Validation and prospective application of allosteric binding site detection and ligand identification

Host Organisation: Janssen

Scientist-in-Charge: Dr. Herman van Vlijmen

contact email: hvvlijme@its.jnj.com

At the Janssen Pharmaceutical Companies of Johnson & Johnson, what matters most is helping people live full and healthy lives. We focus on treating, curing and preventing some of the most devastating and complex diseases of our time. And we pursue the most promising science, wherever it might be found. Janssen Research & Development, LLC discovers and develops innovative medical solutions to address important unmet medical needs in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Please visit http://www.janssenrnd.com/ for more information.

Objectives: We are looking for a skilled and motivated computational chemist for the position of PhD Student, at our Antwerp, Belgium site. The position is part of the EU Horizon2020 project ALLODD, an Innovative Trainings Network (ITN) in the Marie Skłodowska-Curie Actions program.

You will assess how well structure-based methods can identify ligandable allosteric sites and how well ligands for these sites can be identified. For this you will use several conformational sampling methods to identify allosteric sites in disease relevant protein targets. You will apply virtual screening using docking, pharmacophore-based, and AI methods to see if known allosteric ligands can be identified. In addition, you will apply the developed approach prospectively to targets of interest and select compounds for purchase or for synthesis. These compounds will then be tested for activity.

Expected Results/Responsibilities Of The PhD Student Will Include:

1) Develop and execute in silico structure-based methods to identify allosteric binding sites on protein targets. Validate performance on a set of known allosteric modulation sites.

2) Develop and execute in silico methods to identify small molecule allosteric modulators via structure-based and ligand-based methods, both physics-based and AI-based.

3) Collaborate with other PhD students and partners in the ALLODD project.

Planned Secondement(s): Your primary location will be at Janssen in Belgium, and the program foresees two 2-month secondments at other academic partner locations.

• Host1: BRFAA, length 2 months, purpose: training in allosteric modulation at the protein-membrane interface,

• Host2: UNIGE, length 2 months, purpose: training in SWISH methodology for discovering cryptic pockets,

• Host3: UB (Barril), length: 2 months, purpose: Training dynamic undocking and MDmix methodologies to investigate transient allosteric binding sites.

Enrolment in Doctoral degree(s): Yes.

Specific Requirements:

1) Bachelor's or Master's degree in Chemistry, Biochemistry, or related field. Knowledge and strong interest in computational methods.

2) Comfortable with the Python programming language

3) Good multidisciplinary teamwork and communication skills

Bonus qualifications (nice to have, but not required!):

1) Knowledge of organic chemistry

2) Experience with machine learning programming (e.g. PyTorch, TensorFlow)

3) Experience with cheminformatics or computer-aided drug discovery

4) Appointment: The position will be for 4 years.

We will ensure that individuals with disabilities are provided reasonable accommodation to participate in the job application or interview process, to perform essential job functions, and to receive other benefits and privileges of employment. Please contact us to request accommodation.

Johnson & Johnson is an Affirmative Action and Equal Opportunity Employer. All qualified applicants will receive consideration for employment without regard to race, color, religion, sex, sexual orientation, gender identity, age, national origin, or protected veteran status and will not be discriminated against on the basis of disability.

ESR14 : Allosteric modulation of GPCRs at the protein – membrane interface

Host Organisation: UNIURB

Scientist-in-Charge: Prof. Giovanni Bottegoni

contact email: giovanni.bottegoni@uniurb.it

Objectives: Membrane components have recently been characterized as important regulators of membrane protein activity. Lipids exert these effects by directly and specifically binding to the protein surface rather than simply modifying the bilayer biophysical properties. Here, we aim at: 1) systematically characterizing putative binding hot-spots for membrane components (e.g., cholesterol, PIP2, etc) in GPCRs by specifically adapting to the task at hand a multi-scale protocol which we have previously reported (Ferraro et al., Plos ONE 2016). Then, 2) we will target these putative binding sites in virtual ligand screening campaigns. This goal is particularly innovative as we attempt to find drug-like compounds displaying affinity for pockets evolved to lodge lipids (Fu, Bottegoni, et al. Nat Neuroscience 2011).

Expected Results: 1) systematic characterization of binding sites for membrane components (e.g., cholesterol, PIP2, etc.) at the protein–membrane interface in GPCRs. 2) Identification of novel PAMs, NAMs, or SAMs by targeting pockets characterized in (1).

Planned Secondement(s):

• Host1: Heptares, timing M10, length: 3 months, purpose: biophysical and in vitro characterization of selected hits,

• Host2: Merck, timing M20, length 3 months, purpose: training in cell-based and biochemical assays,

• Host3: Charite, timing M30, length 3 months, purpose: Training in X-ray crystallography.

Enrolment in Doctoral degree(s): The ESR will have the possibility to join a three-year PhD program at UNIURB starting Autumn 2022, under the supervision of Prof. Bottegoni (UNIURB) and Dr. de Graaf (Heptares).

Specific Requirements: Previous experience in/knowledge of one or more among 1) medicinal chemistry, 2) coarse grained and/or atomistic molecular dynamics simulations, 3) virtual ligand screening protocols, 4) Python programming is not mandatory but will be considered a plus.