Chemical Space Profiling of SARS-CoV‑2 PL^pro Using DNA-Encoded Focused Libraries

DNA-encoded library (DEL) technology is gaining attention
for its
rapid construction and deconvolution capabilities. Our study explored
a novel strategy using rational DELs tailored for the SARS-CoV-2 papain-like
protease, which revealed new fragments. Structural changes post-DEL
screening mimic traditional medicinal chemistry lead optimization.
We unveiled unique aromatic structures offering an alternative optimization
path. Notably, we identified superior binding fragments targeting
the BL2 groove. Derivative 16 emerged as the most promising
by exhibiting IC50 values of 0.25 μM. Derivative 6, which features an aromatic fragment capped with a naphthalene
moiety, showed IC50 values of 2.91 μM. Molecular
modeling revealed hydrogen bond interactions with Lys157 residue and
potential covalent interactions with nearby amino acid residues. This
research underscored DEL’s potential for fragment-based drug
discovery against SARS-CoV-2 protease.