This study comprehensively analyzes how various inhibitors bind to the SARS-CoV-2 macrodomain Mac1, a key protein implicated in hampering the host's immune response following viral infection. In this study we used volume-based metadynamics simulations to investigate the binding mechanisms of ADP-ribose and two Mac1 inhibitors: the adenineanalogue GS-441524 and the non-adenine-analogue S09. By combining free-energy simulations with a bioinformatic analysis, we aimed at determining whether the binding patterns observed for the selected ligands are conserved can be generalized across Mac1 inhibitors and can be exploited to guide a rational design for future therapeutics. Our simulations show the pivotal role of the adenosine moiety in Mac1 recognition. Notably, for small molecules, like S09 and GS-441524, the oxyanion hole also emerged as an alternative and essential stabilizing region. This site, which preferentially accommodates electronegative groups, is engaged by approximately 76% of reported Mac1 inhibitors, making it a key target for Mac1 inhibition. In addition, we demonstrate that the unstructured loops 1 and 2 shape ligand entry, with loop 1 functioning as a dynamic gateway. Within this loop, Leu126, part of the virus-specific P-L-L-S motif, serves as a key anchoring residue for potent inhibitors. Collectively, these findings suggest that targeting both the oxyanion hole and Leu126 may enhance both the specificity and affinity of next-generation Mac1 inhibitors.