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Targeting myosin for heart disease: a structure-based approach to design conformation-selective modulators

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  • Full or part time
    Dr A Fornili
    Dr Julien Ochala
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Applications are invited for a PhD studentship starting from September 2019 in Dr. Arianna Fornili’s group at Queen Mary University of London and in collaboration with Dr. Julien Ochala at King’s College London. The studentship is funded by the EPSRC Doctoral Training Partnership at Queen Mary University of London.

The aim of the project is to design and test small molecules that can either inhibit or activate cardiac myosin, a key component of the molecular machinery involved in heart contraction. The main outcome will be a new set of potential myosin modulators, to be used as lead compounds in the development of drugs for severe heart conditions such as heart failure or inherited cardiomyopathies.
The ground breaking discovery in 2010 of the heart failure drug Omecamtiv Mecarbil has opened the way to the development of direct sarcomeric modulators, i.e., compounds that can bind to sarcomeric proteins and modify their function. The expected advantages of this type of drugs over more traditional approaches are a reduction of side effects and the possibility to develop more personalised drug therapies using a spectrum of molecules to finely tune the activity of the target.
In this project, a structure-based approach will be adopted for the development of new myosin modulators, were potential candidates will be identified by using computational techniques such as molecular dynamics simulations, molecular docking and virtual screening, and subsequently tested using in vitro motility assays.

Supervisory team: Dr Fornili has unique expertise in the computational study of biomolecular dynamics and in particular of proteins involved in muscle contraction. Recent contributions from the lab include the first theoretical observation of a binding pocket induced by mechanical stress (JCTC, 2018), the development of methods for the prediction of rescue binding pockets in proteins (Bioinformatics, 2018) and the study of the effects of a heart failure drug on cardiac myosin dynamics (PLOS Comp. Biol., 2017). More information can be found at https://afornililab.wordpress.com.
Dr Ochala is a Reader in Physiology at King’s College London. He has unique experience as well as an international reputation in delivering mechanistic muscle studies. He has established a full portfolio of advanced biophysical techniques and continue to publish landmark papers relating to the myosin motor function or cellular mechanics. More information can be found at https://kclpure.kcl.ac.uk/portal/julien.ochala.html.

Techniques and Training: the successful candidate will be trained in different modelling techniques, including molecular dynamics simulations, molecular docking and virtual screening. The student will also have the opportunity to learn scientific programming languages for data analysis such as R and Python.
Training for the experimental part of the project will be provided in Dr. Ochala’s lab at King’s College London, where the student will learn how to perform in vitro motility assays and to test myofibre mechanics.

Environment: Queen Mary University of London (QMUL) is a member of the Russell group and is one of the leading research-focused institutions in the UK. QMUL has been ranked 9th among multi-faculty institutions in the UK for research impact in the last Research Excellence Framework (REF) exercise. All PhD students and Post-doctoral researchers are part of the QMUL Doctoral College, which provides support with high-quality training and career development activities.

Eligibility: Applications are welcome from outstanding students with, or expecting to obtain, a first or upper-second class honours degree in Chemistry, Pharmaceutical Chemistry, Biochemistry, Physics, Biophysics or related disciplines. A masters degree is desirable. Previous experience in molecular modelling/simulation is essential, previous experience in computer programming and/or experimental biophysical techniques is a plus.

Application: Before submitting a formal application online, please contact Dr. Fornili ([Email Address Removed]) and include your CV, your academic transcripts, a cover letter explaining eligibility and interest in the project and the contact details of two academic referees. The deadline for formal applications is on the 31st of January 2019.

Funding Notes

The studentship is funded by EPRSC and will cover tuition fees and an annual tax-free maintenance allowance at the Research Council rate (£16,777 in 2018/19) for 3.5 years. UK students, and EU students who have been ordinarily resident in the UK for at least 3 years are normally eligible for full EPSRC funding. Please see the EPSRC website for further details: https://epsrc.ukri.org/skills/students/help/eligibility/

References

• M. Tiberti, B.-D. Lechner, A. Fornili (2018). Binding Pockets in Proteins Induced by Mechanical Stress. J Chem Theor Comp 10.1021/acs.jctc.8b00755
• M. Tiberti, A. Pandini, F. Fraternali, A. Fornili: In silico identification of rescue sites by double force scanning, Bioinformatics 34 (2018) 207.
• S. Hashem, M. Tiberti, A. Fornili: Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil, PLoS Comp. Biol. 13 (2017) e1005826.
• Jungbluth H, Treves S, Zorzato F, Sarkozy A, Ochala J, Sewry C, Phadke R, Gautel M, Muntoni F The congenital myopathies – inherited disorders of excitation-contraction coupling and muscle contraction. Nat Rev Neurol. 14 (2018) 151.
• Chan C, Fan J, Messer AE, Marston SB, Iwamoto H, Ochala J. Myopathy-inducing mutation H40Y in ACTA1 hampers actin filament structure and function. Biochim Biophys Acta. 1862 (2016) 1453.
• Lindqvist J, Levy Y, Pati-Alam A, Hardeman EC, Gregorevic P, Ochala J. Modulating myosin restores muscle function in a mouse model of nemaline myopathy. Ann Neurol. 79 (2016) 717.
• Ochala J, Sun YB. Novel myosin-based therapies for congenital cardiac and skeletal myopathies. J Med Genet. 53 (2016) 651.

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