Global public health has been a critical problem by the sudden increase of the COVID-19 outbreak. The papain-like protease (PLpro) of SARS-CoV-2 is a key promising target for antiviral drug development since it plays a pivotal role in viral replication and innate immunity. Here, we employed the all-atom molecular dynamics (MD) simulations and binding free energy calculations based on MM-PB(GB)SA and SIE methods to elucidate and compare the binding behaviors of five inhibitors derived from peptidomimetic inhibitors (VIR250 and VIR251) and naphthalene-based inhibitors (GRL-0617, compound 3, and compound Y96) against SARS-CoV-2 PLpro. The obtained results revealed that all inhibitors interacting within the PLpro active site are mostly driven by vdW interactions, and the hydrogen bond formation in residues G163 and G271 with peptidomimetics and the Q269 residue with naphthalene-based inhibitors was essential for stabilizing the protein-ligand complexes. Among the five studied inhibitors, VIR250 exhibited the most binding efficiency with SARS-CoV-2 PLpro, and thus, it was chosen for the rational drug design. Based on the computationally designed ligand-protein complexes, the replacement of aromatic rings including heteroatoms (e.g., thiazolopyridine) at the P2 and P4 sites could help to improve the inhibitor-binding efficiency. Furthermore, the hydrophobic interactions with residues at P1-P3 sites can be increased by enlarging the nonpolar moieties (e.g., ethene) at the N-terminal of VIR250. We expect that the structural data obtained will contribute to the development of new PLpro inhibitors with more inhibitory potency for COVID-19.