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

Project Description

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, with the goal to first develop our knowledge quantitative framework for obtaining the set of requirements on physicochemical and pharmacological characteristics and energetics of interactions for the design of allosteric drug candidates. 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 (Quantum Chemical Topology=QCT). QCT offers a modern energy partitioning scheme that does not suffer from the problems that older schemes have. Hence, IQA gives access to clearly defined energy types: intra-atomic energy (including kinetic energy), electrostatic (beyond point charges), exchange and correlation. The following chemical concepts can be quantified by these IQA energies, respectively: steric effects, ionicity and (a) polarity, a sliding scale of covalency (bond order and (hyper)conjugative effects), and dispersive effects. Much chemical insight ultimately comes down to finding out 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 if any assumptions, and close to the underpinning quantum reality.

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.

Entry Requirements:
Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Singapore, as outlined on View Website.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.


1] “Using the Relative Energy Gradient Method with Interacting Quantum Atoms to Determine the Reaction
Mechanism and Catalytic Effects in the Peptide Hydrolysis in HIV-1 Protease”, J.C.R. Thacker, M.A. Vincent
and P.L.A. Popelier, Chemistry. A European Journal, 24, 11200-11210 (2018).
2] “The ANANKE Relative-Energy-Gradient (REG) Method to Automate IQA Analysis over Configurational Change”,
J.C.R. Thacker and P.L.A. Popelier, Theor.Chem.Accs., 136, 86 (13 pages) (2017).
3] “On the perturbation nature of allostery: sites, mutations and signal modulation”, E. Guarnera and I.N. Berezovsky, Current Opinion in Struct. Biol. , 56, 18-27 (2019).
4] “Toward Comprehensive Allosteric Control over Protein Activity”, E. Guarnera and I.N. Berezovsky, Structure, 27, 866-878 (2019).
5] “Understanding how prolyl-4-hydroxylase structure steers a ferryl oxidant toward scission of a strong C–H bond.”, A. Timmins, M. Saint-André and S. P. de Visser, J. Am. Chem. Soc., 139, 9855-9866 (2017).

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