Cathepsin L is a lysosomal enzyme that, when dysregulated, promotes pathological processes such as tumor metastasis, chronic inflammation, and the entry of certain viruses into cells. This thesis develops novel peptidomimetic inhibitors capable of precisely blocking cathepsin L by combining computational models (molecular docking, molecular dynamics, and hybrid QM/MM simulations) with organic synthesis and in vitro kinetic assays to understand, at the atomic level, how the enzyme-inhibitor complex forms and what determines the type of inhibition that occurs. Four different "warheads" were studied: Michael acceptors (ketovinyl ester and sulfone), stereochemically modulated epoxyketones, more stable ketovinyl amides, and reversible acylhydrazones. The results identify key active site interactions and guide the design of compounds with nanomolar affinity and greater control over reactivity, bringing the development of more selective and safer therapeutic candidates closer.
