The main objective of this research is to develop and apply state-of-the-art Computational tools to achieve an understanding of intermolecular interactions in molecular imprinting of theophylline into complex polymeric systems. Molecular dynamics (MD) simulations were carried out for different molecular systems in order to predict the interaction energies, the closest approach distances and the active site groups between the simulated molecular systems and different bio-ligands. The minimized structures of five ligands, theophylline, and its derivatives (theobromme, theophylline-8-butanoic acid, caffeine and theophylline-7-acetic acid) have been obtained with the use of molecular mechanics approach. NVT MD simulations at room temperature were carried out to obtain equilibrated conformations in all cases. The first simulated molecular systems consisted of a ligand and commonly used functional monomers, polymers and a substrate. The second simulated molecular systems consisted of a ligand and a monomer or polymer using a solvent (ethanol). During this study, it was found that electrostatic interactions play the most significant role in the formation of molecular imprinting materials. The simulated functional monomers and polymers with ligands indicate that the functional groups interacting with ligands tends to be either -COOH or CH2=CH-. It was also found that molecular substrate without functional side groups are recommended for molecular imprinting technology. For both the solvated monomer and polymer systems is that it appears that the presence of the solvent appears. to favour the formation of more stable clusters with theophylline than with its derivatives. (c) 2005 Elsevier Ltd. All rights reserved.