Smith - Modelling molecular interactions
Molecular modelling plays an integral role in the discovery and development of new drugs, being a key component in the process of structure-based drug design, in aiding in the identification of molecules in lead discovery, and in predicting pharmacokinetic properties.
We utilize quantum-mechanical methods to understand enzyme mechanism, molecular mechanical methods to explore the dynamics of proteins, and use a variety of tools to predict how molecules interact.
We employ X-ray crystallography to determine the structures of complexes of proteins, polypeptides, and small molecules.
Modelling peptide foldamer interactions
Incorporation of non-natural amino acids, including b-amino acids and staples, into peptides can be used to engineer structural and proteolytic stability into the molecule. Bim BH3 peptides incorporating a hydrocarbon cross-link and cyclic b-amino acids is able to mimic the native a-helical structure of the Bim peptide, is ~100-fold more resistant to proteolysis, and is able to enter cells to block protein-protein interactions associated with apoptotic signaling.
A biochemical property prediction system
Computational prediction of pharmacokinetic properties of drug candidates has become an integral tool in development of new drugs. The BioPPSy package assembles a set of tools and databases for predicting the physical properties of small molecules. The program determines the correlation between a given property and a collection of molecular and structural descriptors using a training set of molecules. The models generated by this analysis can then be used to predict the properties of compounds during the development of new and novel drugs. The program and its databases are all open-source.
Turning nature’s defenses against human disease
The sea anemone produces a toxin that defends it from its natural predators. This toxin, ShK, can be engineered to bind selectively to human receptors that modulate the immune response. Modelling the interaction of the ShK with potassium channels reveals how the toxin can be modified to improved it binding affinity and selectivity. Selective inhibitors of these potassium channels may have utility in the treatment of auto-immune diseases including multiple sclerosis, rheumatoid arthritis and diabetes.