Molecular models of cancer control
An important progression in the development of cancer is when a localised tumour can spread to other parts of the body. One of the array of molecules that facilitates this process known as metastasis is heparanase. In a cancer, heparanase activity is elevated. Its molecular target is heparan sulphate (HS) which is present in the lining of the endothelium of blood vessels. Increased activity here by the enzyme promotes angiogenesis and subsequent metastasis when the ball of cells has developed an increased blood supply. As one of the keys to cancer treatment, the EU funded project HEPARANASE aimed to study the inhibition of the enzyme. Enzyme action depends on the presence of a specifically-shaped binding site for the enzyme to lock onto its target molecule before products can be released. Knowledge of the actual structure of molecules involved in the pathways then is crucial. The team at the Institute of Chemistry at the Slovak Academy of Sciences performed molecular modelling studies on possible heparanase substrates and inhibitors. In particular, they concentrated on the influence of ions and substituents at key points in the molecules. Quantum chemical and molecular mechanics calculations showed that counter-ions like Na+ have a stabilising effect on the three-dimensional structure of sulphated oligosaccharides like HS. Basically they interact with negative ions such as nitrogen sulphate, -NSO3 and carboxy -COO. These charged interactions seemed to be particularly important at the linkages between sub-units of the sugar chains. The same team refined their research to two particular binding domains of the enzyme with seven different oligosaccharides. Using molecular mechanics and the Monte Carlo conformational method for peptide structure they studied the binding action. Data was collected on the interaction between ligands with a metal electron donor like Na+ and substituted groups on the receptor site. Knowledge of the specificity of the molecular interactions that result in angiogenesis can form the basis for the design of tumour inhibitors. Furthermore, the escalation of the disease can be prevented by blocking the requirements for tumour metastasis at a molecular level.
