Dynamic combinatorial chemistry is defined as “the chemistry under thermodynamic control”. It is based on the combination of building blocks that react with each other through reversible chemical bonds to form the final products, reaching the thermodynamic equilibrium (dynamic combinatorial library, DCL). This chemistry is able to respond to external stimuli such as pH, temperature, or the addition of a biomolecule acting as a template. For instance, adding a template will shift the equilibrium towards the formation of the compounds with higher affinity to the template.Templated-DCLs developed under physiological conditions require an effective design of the dynamic chemical system composed of a biomolecule as a template, reversible chemistry that works effectively under physiological conditions, structurally diverse building blocks compatible with the target, and an analysis method. Protein-directed dynamic combinatorial chemistry (P-D DCC) is currently a powerful and efficient tool for discovering ligands with high affinity to a protein target. In this thesis, adding two different protein targets, NCS1 and glucose oxidase, shifted the DCL equilibrium to forming the best ligands in a pool of compounds…