Abstract: The tick-borne encephalitis virus (TBE) is a neurotrophic disease that has spread more rapidly throughout Europe and Asia in the past few years. At the same time, no cure or specific therapy is known to battle the illness apart from vaccination. To find a pharmacologically relevant drug, a computer-aided drug screening was initiated. Such a procedure probes a possible binding of a drug to the RNA Polymerase of TBE. The crystal structure of the receptor, however, includes missing and partially modeled regions, which rendered the structure incomplete and of questionable use for a thorough drug screening procedure. The quality of the receptor model was addressed by studying three putative structures created. We show that the choice of receptor models greatly influences the binding affinity of potential drug molecules and that the binding location could also be significantly impacted. We demonstrate that some drug candidates are unsuitable for one model but show decent results for another. Without any prejudice on the three employed receptor models, the study reveals the imperative need to investigate the receptor structure before drug binding is probed whether experimentally or computationally. URL