查看文章

The present work reports molecular modelling investigation performed for melatonergic ligands, aimed at the design of new compounds, definition of structure-activity relationships and investigation of the mechanism of action. Some aspects of the binding mode of melatonergic ligands are studied for the first time exploiting three-dimensional structures of the two melatonin receptors, which were released just before the beginning of the Thesis. While providing a new starting point for structure-based drug design, experimental structures are representative of free-energy minima which are rarely escaped within unbiased molecular dynamics simulations. However, configurations far from these minima could hide important information for design of compounds of pharmaceutical interest. Therefore, free-energy differences must be assessed by either observing the probability of an alternative state to spontaneously occur in …