Chemical Space Profiling of SARS-CoV-2 PL pro Using DNA-Encoded Focused Libraries.
Xudong WangYing ZhuQingyi ZhaoWeiwei LuYechun XuHangchen HuXiaojie LuPublished in: ACS medicinal chemistry letters (2024)
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 IC 50 values of 0.25 μM. Derivative 6 , which features an aromatic fragment capped with a naphthalene moiety, showed IC 50 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.
Keyphrases
- sars cov
- amino acid
- drug discovery
- respiratory syndrome coronavirus
- single cell
- circulating tumor
- cell free
- single molecule
- working memory
- human health
- cancer therapy
- high resolution
- anti inflammatory
- smoking cessation
- water soluble
- climate change
- quantum dots
- transcription factor
- coronavirus disease
- mass spectrometry
- transition metal
- visible light