Research Interests
Molecular Modelling and Drug Docking
The structural modelling of proteins implicated in breast cancer, such as the PI-3 Kinase family is vitally important for the precise understanding of ligand specificity and therefore drug analysis and design. Already a number of successful collaborations have been carried out at Breakthrough.
The phosphoinositide 3-kinases (PI3-Ks) constitute a family of lipid kinases involved in the regulation of a network of signal transduction pathways that control a range of cellular processes. PI3-Ks are classified into four distinct subfamilies based upon their substrate specificities. Of these, only the class I isoforms are capable of utilizing PtdIns(4,5)P2 as a substrate to produce the lipid second messenger PtdIns(3,4,5)P3. Three class IA PI3-Ks exist: these possess a p110∝, p110β, or p110 SIGMA? catalytic subunit in complex with one of three regulatory subunits, namely p85a, p85b or p55d.
There is also a single class IB PI3-K, which comprises a p110γ catalytic and a p101 regulatory subunit. PI3-Ks have been the subject of growing attention over recent years, having been implicated in a range of therapeutic areas including oncology. Accordingly, a body of literature outlining the discovery of small molecule inhibitors of these enzymes has begun to emerge, and a number of structurally-distinct classes of small molecule, ATP-competitive inhibitors displaying selectivity within the class I subfamily have been reported.
In a previous study we have performed structural docking and modelling studies with several distinct small molecule PI3-K inhibitors that exhibited subtype selectivity. We have identified two specific residues in the ATP binding pocket that are different in all four subclasses. In collaboration with Leslie-Ann Martin we propose to mutate the two residues in p110γ in order to convert it into a more p110β selective enzyme. The effect of these mutations on binding efficiency of the PI3K inhibitors will be measured and the IC50 values for the inhibitors will be determined.
Find out more about Dr Marketa Zvelebil's research on the Breakthrough Breast Cancer website
Mathematical Modelling of Specific Networks
The Wnt family of proteins plays a major role in controlling cell proliferation, cell-fate determination and differentiation during embryonic development and adult homeostasis. It has also been suggested that the Wnts activate a number of different signalling pathways.
Sequencing Pipelines and Meta Analysis
Together with the integration of the basic free software analysis pipeline, Cancer Informatics has developed and integrated a range of data analysis solutions.
