Lipocalin family proteins have been shown to bind a vast array of small molecules and have subsequently been adapted to selectively bind specific ligands. In this study, candesartan, an antihypertension drug, was identified to bind mouse and human siderocalin in biomolecular NMR experiments, allowing for structural insights into the candesartan-siderocalin interaction. The ligand binding site was determined through an integrative structural biology approach using in silico ligand docking guided by NMR experiments. Building on this structurally informed binding model, we used rational protein design to modulate the binding pocket for increased or decreased ligand binding affinity. The predicted mutations were evaluated in vitro using isothermal titration calorimetry. This resulted in a mutant with a 50-fold increase in binding affinity in addition to a second mutant with a five-fold decrease in binding affinity. Thus, siderocalins have potential as a scaffold for creation of various ligand binding-based tools, including drug scavengers.