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  (A*STAR Split-site) Rules for the design of allosteric effectors: chemistry and interactions


   Department of Chemistry

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  Prof P Popelier, Dr Igor Berezovsky  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Allosteric drugs have become an indispensable toolbox of rapidly developing precision medicine, having already established a reputation of advantages over traditional medicine. At the same time, there is an increasing understanding that allosteric sites and modulators should also be quite different from the traditional ones, including specific requirements for their pharmacophore characteristics, different solubility, membrane permeability, aggregation and binding characteristics, and structure‐activity relationship (SAR). Therefore, the progress in design of allosteric drugs strongly depends on building new libraries of allosteric compounds with corresponding characteristics and on modifying or fully revising the fragment screening, structure‐based docking, and other relevant techniques. Finally, the convolution of signalling between the allosteric and functional sites should be formalised in model that allow predictions of regulation from first principles.

This project is aimed to tackle the challenges above. In particular, we will apply the Manchester‐developed Relative Energy Gradient (REG) method to sites in systems chosen by Singapore. REG is able to compute chemical insight from protein‐ligand interaction, at atomistic level. REG achieves this by using the concept of topological atoms. The corresponding modern energy partitioning called Interacting Quantum Atoms (IQA) gives access to clearly defined energy types: intra‐atomic energy, electrostatic, exchange and correlation. The following chemical concepts can be quantified by these IQA energies, respectively: sterics, ionicity and polarity, covalency (bond order and (hyper)conjugative effects), and dispersion. Chemical insight derives from knowing which fragment of a total system behaves like the total system, in terms of an energy profile. This is exactly what REG accomplishes, with minimal assumptions, if any.

There will be four major stages to the project: 1. learning distinct features of orthosteric and allosteric sites; 2. establishing a set of rules archetypal for allosteric effectors and interactions with corresponding sites; 3. proof‐of‐principle design of some site‐effector interactions; 4. exploring the allosteric signalling caused by the interactions of candidate‐ligands with newly found or designed allosteric sites.

The synergy between different expertise of the Manchester and Singapore groups will allow to pave the whole way from the prediction of allosteric sites to targeted design of allosteric ligand candidates with required characteristics, and quantification of the allosteric signalling as a result of ligand binding. Kinases are selected as a model system in this project, because their structural conservatism and, at the same time, existence of four types of regulatory sites that make design of traditional drugs very hard, while allowing to explore allosteric archetypes.

Eligibility

Applicants should have, or expect to achieve, at least a 2.1 honours degree or a master’s in a relevant science or engineering related discipline.

 Funding

Scholarships are available for suitable candidates to commence on this 4-year programme in October 2024 including:

·        Tuition fees

·        Annual stipend at the minimum UKRI rate (2023/24 rate £18,622) to the students when in Manchester (for a maximum of 2 years) and when in A*STAR (two years) equivalent to S$2,700/month.

·        Flight allowance for students travelling to Singapore (£1,000) paid by University of Manchester.

·        One return airfare to/from Singapore (S$1,500) paid by A*STAR

·        Medical insurance and settling-in allowance (S$1,000) paid by A*STAR

·        An annual Research Training Support Grant (RTSG) towards project running costs/consumables (up to £5,000 pa) provided to all students when in Manchester.

Supervisor travel allowance up to £6,000 for two airfare/accommodation visits to Singapore. 

  Before you apply

We strongly recommend that you contact the supervisor(s) for this project before you apply.

How to apply

To be considered for this project you’ll need complete a formal application through our online application portal.

When applying, you’ll need to specify the full name of this project, the name of your supervisor, how you’re planning on funding your research, details of your previous study, and names and contact details of two referees.

Your application will not be processed without all of the required documents submitted at the time of application, and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered.

If you have any questions about making an application, please contact our admissions team by emailing

[Email Address Removed].

Equality, diversity and inclusion

 Equality, diversity and inclusion are fundamental to the success of The University of Manchester, and are at the heart of all of our activities. We know that diversity strengthens our research community, leading to enhanced research creativity, productivity and quality, and societal and economic impact.

 We actively encourage applicants from diverse career paths and backgrounds and from all sections of the community, regardless of age, disability, ethnicity, gender, gender expression, sexual orientation and transgender status.

 We also support applications from those returning from a career break or other roles. We consider offering flexible study arrangements (including part-time: 50%, 60% or 80%, depending on the project/funder).

Biological Sciences (4) Chemistry (6) Computer Science (8) Mathematics (25) Physics (29)

Funding Notes

See project description for funding notes

References



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