The use of small-molecule ligands to control biological activities at the molecular level is expected to lead not only to an essential understanding of cellular systems but also to the development of applications in medicine and diagnosis. In the conventional search for small molecule drugs, there is often insufficient information on the mechanism of action at the molecular level for the selected candidate compounds. Therefore, evaluation of the specificity of the candidate drug to the target molecule is an important step. Therefore, we hypothesized that it is crucial to capture the "quality of the interaction" that can create specificity in the binding mode even if the affinity is low, and those thermodynamic indices can capture this quality. Here, we conducted compound selection by thermal measurement using ITC and were able to select compounds with activity against the target protein in vitro and in the cell. This method is expected to create new compounds with specific binding modes that have been overlooked in conventional screening due to their low affinity.