Hunter syndrome or Mucopolysaccharidosis II is an inherited X linked disease, caused by mutations in iduronate 2 sulfatase (IDS), enzyme which catalyzes the initial step reaction of heparan and dermatan sulfate degradation. Allelic heterogeneity in MPSII challenges genotype-phenotype correlation. With the aim of understanding the repercussion of mutations on enzyme structure-function, we performed protein modeling and docking simulations with wild and mutant forms of hIDS. Mutations were obtained from a molecular study conducted in Colombian patients. Point mutations affected substrateprotein interactions. In the case of S71N (attenuated phenotype) further experimentation is required. Novel mutants P160SfsX4, D190Pfs13X and P185GfsX2 have a severely distorted conformation. Detailed analysis of the ligand-protein interaction is also of great significance in designing molecules for treatment. This is the first report of molecular docking performed with wild and mutant forms of iduronate-2-sulfatase as a bioinformatical approach to phenotypegenotype correlation in patients with Hunter Syndrome in Colombia. © Springer International Publishing Switzerland 2014.