ref. HYMS201313
	•	Main location: Hull
	•	Closing date: 31 May 2013
This PhD Scholarship in Cardiovascular and Metabolic Research is for the specific project: Modelling of the aryl hydrocarbon receptor (AHR) ligand binding domain for virtual screening of isoflavones


PROJECT DETAILS
Computer modelling of the interactions between protein receptors and ligands is a field of computational chemistry in constant development, mainly due to the importance of the atomistic level of detail it provides for rational drug design. A number of approaches have been developed, mainly by the pharmaceutical industry, that allow “screening” of a large number of ligands for a given receptor and have been shown to often shorten the path from drug design to its commercialisation. Many techniques rely on approximate and/or known interaction patterns and thus are inefficient for non-standard receptors. In this work, we will explore a bespoke technique that tries to provide accurate, interaction information based on quantum chemical information at the density functional level of theory. Our model does not require any a priori knowledge of the binding mode of the ligands to the receptor and as such is ideal for very general receptors such as the dioxin/aryl hydrocarbon receptor.

The dioxin/aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor responsive to both natural and man-made environmental compounds. The aryl hydrocarbon receptor (AhR) family of transcriptional regulators controls a variety of developmental and physiological events, including toxin metabolism, alterations in endocrine homeostasis, cellular proliferation and tissue differentiation; these responses are associated with adverse health effects. Dioxins and related compounds have been demonstrated to alter cell growth and differentiation, and to affect homeostasis and hormone balance by modulating the induction of enzymes, growth factors and hormones as well as their cognate receptors

Dietary factors that modulates ArH receptors
Many studies report effects of bioactive compounds on various physiological functions and pathways via their anti-oxidative and anti-inflammatory properties, and others report their ability to act as ligands for important cell receptors such as the steroid hormone receptors or the AhR. These bioactive compounds are mainly polyphenols such as flavonoids (with their important subclass of phytoestrogens), indole compounds, or organosulfur compounds.

Thus far, exactly which ligands may interact with the aryl hydrocarbon receptor remains unknown, but the AhR is known to bind several exogenous ligands such as natural plant flavonoids, polyphenolics and indoles, as well as synthetic polycyclic aromatic hydrocarbons and dioxin-like compounds. This project will use state-of-the-art atomic-scale simulations and first-principle calculations to determine the precise mode of interaction of ligands to AhR, and then derive a model that is suitable for describing the interaction between the AhR and different dietary polyphenols, isoflavones and some of their metabolites. This will include molecular dynamics simulations of the receptor to account for the flexibility of the binding pocket, combined with periodic density functional calculations on part of the system to obtain an in depth description of the drug-receptor interaction. We will also investigate the binding of a number of ligand metabolites in order to obtain a more realistic picture of AhR binding in realistic biological conditions.

The predictive model may then be translated to in vitro studies to prove that the model is valid but this is not the primary aim of this PhD study.

LOCATION
The academic work will be based in HYMS Centre for Cardiovascular and Metabolic Research at the University of Hull campus.

RESEARCH CULTURE
This PhD is funded through the Hull York Medical School and is a joint project with chemistry on in silico modeling of the aryl hydrocarbon receptor. The PhD will be based in the department of chemistry with Dr David Benoit and jointly supervised by Professor Stephen Atkin 

NAMED ACADEMIC
Professor. Stephen Atkin ([log in to unmask] ). Interested applicants can informally consult with Professor Atkin about the project.

FUNDING
This PhD Scholarship includes fees at the 'Home/EU' student rate and an annual stipend for three years, depending on satisfactory progress.

START DATE
The start date has not yet been confirmed and can be agreed by mutual consent.

QUALIFICATION REQUIRED
A minimum of a 2:1 BSc, computer modelling experience would be advantageous.

HOW TO APPLY?
All applications MUST BE submitted to the HYMS Postgraduate Centre via the online application method: 
http://www.hyms.ac.uk/postgraduate/applying-for-postgraduate-study.aspx
Please quote REF HYMS201313 with the scholarship title when applying. In order for the Panel to get a sense of your academic background, commitment and interest, you are required to complete the application form in full and provide a research proposal/outline of academic interest.
If you have any queries on how to apply please email [log in to unmask]

INTERVIEW DATE
Applicants who are shortlisted for interview will be sent details of time and venue via email immediately after the deadline. If you are not invited for the interview, it means that your application has not been successful. Please note that we do not offer feedback to applicants who are not invited to the interview.

INTERVIEW OUTCOME
As soon as reasonably practicable after the interviews have taken place HYMS will write to the successful applicant offering him/her the post. Upon receipt of formal written acceptance of the post we will write to notify unsuccessful candidates. Whilst we try to do this in as effective and efficient manner as possible, sometimes the process can take rather longer than is ideal because of the need to recall candidates for a second interview and reconvene interview panels and/or due to routine disruptions caused by leave and other absences. We apologise for any delay and inconvenience caused in these circumstances.

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