The Severe Acute Respiratory Syndrome (SARS) emerged in 2003 in Asia, and within a few months infected 8500 people world and caused more than 800 deaths. This novel medical condition is a viral respiratory illness caused by the SARS-associated coronavirus (SARS-CoV). And at present, no efficacious therapy is available, for these reason finding a useful drug candidate against SARS corona virus is a goal with high scientific, technological and socio-economic interest. Our (and other´s) preliminary results indicate that the viral protease is an excellent target for the treatment of coronaviral infections. In order to obtain new active SARS-CoV molecules as main protease inhibitors Dynamic Ligation Screenig (DLS) methodology will be developed. This new approach combines dynamic, target-assisted formation of inhibitory species and detection by fluorescence-based screening methodology. In addition to use an enzymatic reaction for fragment detection amplifies the signals and thus reduces the required amount of protein drastically. Finally, enzymatic detection via a fluorescent reporter molecule should enable high-throughput screening (HTS) in microtiter plates. Based on preliminary results, the synthesis of structural analogues of peptide-aldehydes, that containing in the C-terminal extreme other functionalities, will be synthesized. The reaction of these analogues of peptide-aldehydes, acting as directing probe, with a library of amines, carboxylic acid and isocyanides in presence of the enzyme, their substrate in water through Mannich and Ugi reactions provides -amino carbonyl and -N-acylamino amides compounds. The analysis of the crude reaction mixtures will be carried out employing fluorescence assay and it will be allowed us find active fragments (Hits). In these cases, it will be transform through “reversed” screen until obtain one non-peptidic inhibitor. Finally, molecular modelling studies will be realized to determinate both structure-activity relationship.