Computer-aided drug design and computational chemistry
Research activities
These groups use molecular graphics and associated computational modelling techniques for a variety of applications including:
- Development and application of computational techniques for prediction of free energies of binding and solvation
- Development and application of new methods for carbohydrate computational chemistry
- Biomolecular simulation studies of proteins, sugars and DNA
- QM/MM studies of the condensed phase
- Homology/similarity modelling to obtain 3-dimensional structures for proteins we are interested in as targets for drug design, to design mutations or to study potential interactions with other proteins or nucleic acids
- Designing lead drug structures and molecules which bind to enzyme active sites, to DNA in the minor groove or to tRNA and ribozymes
- Designing novel molecular diagnostics based on new approaches to fluorescence using exciplexes
- Re-designing proteins for molecular engineering, for example to produce variants of Green Fluorescent Protein that can be specifically chemically labelled to register enzyme action, such as the action of caspase 3 inside cells undergoing apoptosis
- Designing molecules with novel chemical activities such as DNA cleavage
- Understanding the conformational properties and energetics of small molecules
- Determining high-resolution structures of chemically modified nucleic acids or of DNA: drug complexes using full distance geometry restraints combined with high- field NMR structural determinations of nucleic acid structures
- Understanding how families of ligands dock into binding sites of macromolecules
Structure-based drug design
Within many of the rational drug design projects in the group, computer-aided methods, such as virtual screening and de novo design techniques, play an important role. These projects involve the School's computational chemistry group, led by Dr Richard Bryce. His group also develops new computational approaches, with a focus on molecular dynamics, solvation, hybrid QM/MM methods and carbohydrate modelling.
NMR spectroscopy in conjunction with molecular modelling and other spectroscopic methods allows investigations (by Professor Ken Douglas and Dr Elena Bichenkova) to be made into molecular mechanisms of ligand-target recognition at the atomic level. This provides a description of the region of target and drug surfaces involved in the interaction and important contacts between drug and target responsible for affinity and specificity. The structural analysis of DNA/RNA-ligand interactions by high-field NMR is crucial to define structure-function correlations. This information is a necessary component in the design of novel therapeutics and in prediction of interactions of drugs with the targets.
For example, the group can analyse the shapes of macrolide antibiotics bound to ribosomes (Dr Jill Barber). Also over the years, the group has studied details of binding of ligands to the minor groove of DNA, such as Hoechst 33258, or to tRNA. NMR methods are also used by the group to study interactions of proteins with ligands (Dr Elena Bichenkova, Dr Jill Barber and Professor Ken Douglas). There is 300 MHz instrumentation in the School, and the group has shared usage of 500 MHz high-field instruments housed in the Department of Chemistry. The group collaborates extensively with Professor Gareth Morris, inventor and pioneer of many modern NMR techniques, thereby bringing novel techniques to bear on red biological problems (Dr Jill Barber).