The severe acute respiratory syndrome coronavirus (SARS-CoV/CoV-2) genome encodes 16 non-structural proteins (nsps), which coordinate cell remodeling, virus replication and participate in viral evasion. Notably, nsp3 contains a protein module termed Macro domain, which carries IFN antagonist activity that interferes with host innate immunity response. This domain is able to bind and hydrolyze ADP-ribose derivatives. This activity is correlated to viral escape and thus makes Macro domains a valuable therapeutic target. In the present paper, we report a SARS-CoV Macro domain structure in complex with a MOPS molecule. Based on our structural data, molecular docking was performed on a set of MOPS analogs in the ADP-ribose binding pocket. We present an ELISA-based assay to select hits based on the inhibition of recombinant SARS-CoV/CoV-2 Macro domain-ADP-ribose complex formation. Among the tested analogs, MOPSO and CAPSO are the more efficient in inhibiting ADP-ribose-binding. Structural analysis of these molecules in the ADP-ribose pocket reveals potential interactions with amino acid residues involved in the coordination of ADP-ribose. Overall, these findings suggest that MOPSO and CAPSO bear potential to be used as a scaffold for the design of Macro domain-specific inhibitors.