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  Computational and machine learning driven development of new polysialyltransferase (ST8SiaII) inhibitors against metastatic cancer


   Faculty of Life Sciences

  ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Polysialic acid (polySia) is a carbohydrate polymer important for embryonic development. PolySia is absent in healthy adult tissues whereas overexpressed in several tumours. The high expression of PolySia-NCAM (neuronal cell adhesion molecule) is strongly associated with poor clinical prognosis and several cancers such as lung cancer, pancreatic cancer, neuroblastoma, and gliomas. The synthesis of polySia is mediated by two polysialyltransferases (polySTs): ST8SiaII and ST8SiaIV. In particular, ST8SiaII is of great importance due to its high expression in several tumours which can be thus targeted for selective inhibition, further presenting a new therapeutic opportunity to treat metastatic cancer. Our previous work has demonstrated the druggability of ST8SiaII. We already have established in vitro and in vivo models for the screening of new compounds.

The project is driven by advanced in silico modelling as following:

1. Structure-based design

Techniques such as homology modelling, high throughput virtual screening, molecular docking (HTVS), binding free energy calculations, prediction of pharmacokinetic properties and molecular dynamics simulations will be employed to screen and prioritize drug-like small molecules that could bind to the substrate binding site of ST8SiaII (relative to in-house inhibitor CMP). The promising hit compounds will be purchased/synthesized and will be tested experimentally.

2. Machine learning

Multiple machine learning models will be developed based on the chemical information of the existing ST8SiaII inhibitors. The best model will be combined with HTVS to score and screen potential hit compounds that could bind selectively to ST8SiaII over other isoforms such as ST3Gal-III, ST3GaI-IV and ST6Gal-I.

3. Development of protein – protein interaction inhibitors

ST8SiaII forms key protein-protein interactions with NCAM which are crucial for polysialylation. A consensus protein – protein docking approach will be implemented to develop ST8SiaII – NCAM interaction models, followed by oligopeptide docking and construction of pharmacophore models to eventually identify new peptides/compounds disrupting the protein – protein interaction.

How to apply

Formal applications can be made through the University of Bradford web site. Applicants should register an account, and choose 'Full-time PhD in Cancer Therapeutics' as the course.

About the University of Bradford

Bradford is a research-active University supporting the highest-quality research. We excel in applying our research to benefit our stakeholders by working with employers and organisations world-wide across the private, public, voluntary and community sectors and actively encourage and support our postgraduate researchers to engage in research and business development activities.

Faculty of Life Sciences

The faculty comprises a mixture of academic divisions, research centres and outreach facilities. We provide high-quality teaching with a professional focus and engage in cutting-edge research – which we seek to apply through our extensive links with industry and business. We also offer a wide range of postgraduate taught and research courses.

Many of our academics are active researchers and international research experts.

Our interdisciplinary research themes are focus on:

  • Computational and Data-driven Science
  • Interface of Chemistry Biology and Materials
  • Health, Society, People and Place
  • The Life Course

Our research centres include:

  • Centre for Pharmaceutical Engineering Science
  • Digital Health Enterprise Zone
  • Institute of Cancer Therapeutics
  • Wolfson Centre for Applied Research

University investment in research support services, equipment and infrastructure provides an excellent research environment and broad portfolio of developmental opportunities.

Positive Action Statement

At the University of Bradford our vision is a world of inclusion and equality of opportunity, where people want to, and can, make a difference. We place equality and diversity, inclusion, and a commitment to social mobility at the centre of our mission and ethos. In working to make a difference we are committed to addressing systemic inequality and disadvantages experienced by Black, Asian and Minority Ethnic staff and students.

Under sections 158-159 of the Equality Act 2010, positive action can be taken where protected group members are under-represented. At Bradford, our data show that people from Black, Asian, and Minority Ethnic groups who are UK nationals are significantly under-represented at the postgraduate researcher level. 

These are lawful measures designed to address systemic and structural issues which result in the under-representation of Black, Asian, and Minority Ethnic students in PGR studies.

Biological Sciences (4) Chemistry (6) Computer Science (8) Medicine (26)

Funding Notes

This is a self-funded PhD project; applicants will be expected to pay their own fees or have a suitable source of third-party funding. A bench fee of £5000 per year applies to this project, in addition to tuition fees. UK students may be able to apply for a Doctoral Loan from Student Finance for financial support.


References

1. Jha V, Holmelin FL, Eriksson LA. Binding Analysis and Structure-Based Design of Tricyclic Coumarin-Derived MTHFD2 Inhibitors as Anticancer Agents: Insights from Computational
Modeling. ACS Omega. 2023 Apr 12;8(16):14440-14458. https://doi.org/10.1021/acsomega.2c08025
2. Jha V, Biagi M, Spinelli V, Di Stefano M, Macchia M, Minutolo F, Granchi C, Poli G, Tuccinardi T. Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening Study. Molecules. 2020 Dec 26;26(1):78. https://doi.org/10.3390/molecules26010078
3. Falconer RA, Errington RJ, Shnyder SD, Smith PJ, Patterson LH. Polysialyltransferase: a new target in metastatic cancer. Curr Cancer Drug Targets. 2012 Oct;12(8):925-39. http://dx.doi.org/10.2174/156800912803251225
4. Al-Saraireh YM, Sutherland M, Springett BR, Freiberger F, Ribeiro Morais G, Loadman PM, Errington RJ, Smith PJ, Fukuda M, Gerardy-Schahn R, Patterson LH, Shnyder SD, Falconer
RA. Pharmacological inhibition of polysialyltransferase ST8SiaII modulates tumour cell migration. PLoS One. 2013 Aug 9;8(8):e73366. doi: 10.1371/journal.pone.0073366.
https://doi.org/10.1371/journal.pone.0073366
5. Close BE, Mendiratta SS, Geiger KM, Broom LJ, Ho LL, Colley KJ. The minimal structural domains required for neural cell adhesion molecule polysialylation by PST/ST8Sia IV and ST8SiaII/ST8Sia II. J Biol Chem. 2003 Aug 15;278(33):30796-805. doi: 10.1074/jbc.M305390200. https://doi.org/10.1074/jbc.M305390200

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