Optimization of SARS-CoV-2 M^pro Inhibitors by a Structure-Based Multilevel Virtual Screening Method.

ABSTRACT: With the aim of developing novel anti-SARS-CoV-2 drugs to address the ongoing evolution and emergence of drug-resistant strains, the reported SARS-CoV-2 M^pro inhibitor WU-04 was selected as a lead to find novel, highly potent, and broad-spectrum inhibitors. Using a fragment-based multilevel virtual screening strategy, 15 hit compounds were identified and subsequently synthesized. Among them, A5 (IC₅₀ = 1.05 μM), A6 (IC₅₀ = 1.08 μM), and A9 (IC₅₀ = 0.154 μM) demonstrated potent SARS-CoV-2 M^pro inhibition comparable to or slightly weaker than WU-04. Antiviral activity evaluations revealed that compound A9 exhibited the strongest antiviral activity with an EC₅₀ value of 0.18 μM, quite c

SUBMITTER: Jing L 

PROVIDER: S-EPMC11765572 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature