Studies on generating artificial macromolecular receptors by molecular imprinting of synthetic polymers significantly emerged in the literature during last decades. The noncovalent approach, one of the three methods used in MIP synthesis, is more flexible for the choice of functional monomers, possible target molecules, and use of the imprinted materials. This study aims to investigate a serotonin imprinted polymer prepared by non-covalent approach using molecular modeling. The calculations were carried out by using density functional theory at omega B97XD/6-31++G(d,p) level and the polarizable continuum model was used for solvent calculations. Computational results showed that DMSO plays an important role in the MIP formation as it seems to control the size and the shape of the cavity. DMSO performs these tasks through hydrogen bonding and dispersive interactions. Although experimental IR could not verify the specific interaction modes because of broadband structure, computational IR results showed these modes clearly indicating the interactions leading to MIP formation. This model is specific to the studied serotonin-acrylamide-DMSO system but further studies may reveal a general computational protocol for other MIP systems.