Antiangiogenic Factor Endostatin Studied by Molecular Dynamics

Tumor growth depends on its capacity to induce formation of new blood vessels [1]. Endostatin, a 20-kDa C-terminal fragment of collagen XVIII, is a potent antiangiogenic agent, fully inhibiting tumor growth in mouse models [2]. Since 2000, endostatin has been tested in patients as an experimental therapeutic agent. Results of clinical trials show that tumor size is not reduced under endostatin administration in the majority of patients. Only in one patient, who received a 20-fold higher dose, there was some response. These results suggest the necessity of finding new ways to enhance endostatin inhibitory effects. One strategy is to understand its mechanism of action, unknown at present, which may help on the development of new drugs with higher therapeutic effectiveness. In Molecular Dynamics simulations using the software THOR [3], we found that the Zn ion, present in the crystallographic structure of human endostatin, raises substantially the total surface area occupied hydrophobic amino acids. This result suggests a role for this metal in the regulation of affinity and specificity for heparan sulfate glycosaminoglycans containing interruptions in sulfation patterns. Dimers found in crystals of the human protein were initially attributed to the endostatin/Zn ion complex [4]. At present we are studying the endostatin dimer form by Molecular Dynamics and verifying its stability in solution.