This is an industrially funded 4-year PhD project, in collaboration with Astex Pharmaceuticals and AstraZeneca. It includes a one-year placement in Oxford, during which in-depth training will be provided in fundamental theory, software development, and computational chemistry simulations. This training will be delivered by academics from the Universities of Southampton, Bristol and Oxford via the Centre for Doctoral Training in Theory and Modelling in the Chemical Sciences. Successful completion of year one will lead to the award of an Oxford MSc, and progression to a 3-year PhD research project, which will be based in Southampton, and will include close collaboration with the industrial sponsors.

This project will offer unique exposure to both academic and industrial research environments and is ideally suited to applicants who wish to make an impact in problems of real practical relevance.

Project title: Stabilisation of bio-active ligand conformers using high-level free energy calculations

When a ligand binds to a protein active site, it pays a free energy penalty because it loses many degrees of conformational freedom and because the protein-bound state may not be the lowest energy state of the ligand. An effective strategy to improve the potency of a lead compound in a structure-based drug design project is to stabilise its protein-bound conformation. For relatively simple molecules quantum chemistry energy calculations can be used to estimate the conformational penalty, for example by calculating the energy profile for a key torsion angle in the ligand. Often, however, the situation is more complex, for example when the ligand forms significant intramolecular interactions. In such cases extensive conformational sampling is required with approaches such as classical molecular dynamics, but the interactions involved can be complex in nature, e.g. pi-pi stacking, and hence difficult to capture with standard molecular mechanics force fields. Also, water often plays a key role, especially in the entropic component of the conformational penalty.

The goal of this PhD project is to address this grand challenge in the area of drug discovery by developing hybrid free energy methods that combine the high accuracy of quantum mechanics with the ability of molecular mechanics for extensive sampling of structures via molecular dynamics and Monte Carlo techniques. As far as we are aware this approach has not been attempted before and therefore represents a great opportunity to make an impact in the computational drug discovery field. The developed methodologies will be validated against experimental data – affinities, NMR data and X-ray structures – provided by the industry partners.

Candidate requirements:

UK or EU citizen fully funded

Successful applicants to TMCS typically hold a first class honours degree (or equivalent) in Chemistry or a closely related discipline.
Funding: Full funding of fees and stipend for 4 years. Applications are accepted from self-funded international applicants, but funding restricted to UK/EU applicants only.
Contacts:
Project queries: Professor Chris-Kriton Skylaris, c.skylaris@soton.ac.uk
Professor Jonathan W. Essex, j.w.essex@soton.ac.uk