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Drug binding affinity predictions to achieve targeted drug discovery

Project Description

Molecular modelling and related computational techniques (often referred to as in silico approaches) are an integral part of the drug discovery and development workflow.

Within this framework, we aim at exploiting advanced computer simulations to predict the effect of drugs on proteins and nucleic acids targets.

Specifically, the aim is to develop a predictive computational platform to understand the mechanisms of drug-target association and compute the associated binding free energy (BFE) and kinetics in challenging targets.

While the initial selection of drugs includes established anticancer molecules such as cisplatin and arsenic trioxide, the targets are membrane proteins (eg aquaporins), non-canonical DNA secondary structures (G-quadruplexes) and enzymes (eg phosphatases) involved in cancer cells growth and invasion.

The supervisors have already published in this area and, recently, were the first to apply metadynamics approaches to the investigation of anticancer metallodrugs’ interactions with biomolecules.

The theoretical results will be validated by experimental spectroscopic and biophysical methods established in our groups to achieve drug/target binding free energies and to characterise the overall system at a molecular/atomic level.

Project aims and methods

The project is organised into two main work-packages:

Investigation of the interactions of small-molecules with nucleic acids

Based on our recent work (Wragg et al. Angewandte chemie Int. Ed. 2018), we will continue the development of metadynamics approaches and their validation to achieve the design of selective DNA G-quadruplexes (G4s) stabilisers with anticancer activities.

To confirm the computational predictions, we will apply different biophysical methods (eg FRET, NMR, CD, UV-Vis spectroscopy) to study the interactions and the binding affinity of various small molecules with different G4s.

Investigation of metallodrugs interactions with protein targets

The mechanisms of inhibition of the membrane proteins aquaporins, water and glycerol channels with essential roles in physiology as well as in cancer cells proliferation, by gold-based compounds will be investigated via advanced molecular dynamics (MD), metadynamics and quantum mechanics/molecular mechanics QM/MM methods.

The same approach will be used to study the mechanisms of glycerol and hydrogen peroxide transport across these protein channels.

Start date: 1st October 2019


Professor Angela Casini -

Dr Stefano Leoni -

Funding Notes

Full awards (fees plus maintenance stipend) are open to UK Nationals and EU students who can satisfy UK residency requirements. To be eligible for the full award, EU Nationals must have been in the UK for at least three years prior to the start of the course for which they are seeking funding, including for the purposes of full-time education.

For more information please click on the link below

How good is research at Cardiff University in Chemistry?

FTE Category A staff submitted: 23.00

Research output data provided by the Research Excellence Framework (REF)

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