Abstract The macrodomain of the Chikungunya virus NSP3 protein (ChikV Mac1) hydrolyzes mono-ADP ribose post-translational modifications on the human host proteins. Mutations in Mac1 reduce ChikV virulence. Thus, ChikV Mac1 is a viral drug target. While no potent ChikV Mac1 inhibitors are available, high-affinity inhibitors were developed for Mac1 in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we rationalize this difference in the ligand binding affinity in terms of three differences in the binding site structure and dynamics. First, the apo ChikV Mac1 binding site exhibits substantially more conformational heterogeneity than that of SARS-CoV-2, based on microsecond-scale molecular dynamics simulations; it also has a less druggable binding site, based on program SiteMap. Second, water binding sites overlapping with the ligand binding site in ChikV Mac1 are predicted by program WaterMap to have a stronger affinity for water molecules than the corresponding sites in SARS-CoV-2 Mac1, thus decreasing ligand binding affinity. Finally, a smaller number of Mac1 residues interacts persistently with ADP-ribose in holo ChikV Mac1 than in SARS-CoV-2. With these rationalizations in hand, we designed ligands of ChikV Mac1 using a fragment growth strategy; subsequent molecular dynamics simulations of a representative ligand in complex with ChikV Mac1 substantiated our design.