Structure- and Ligand-Based Discovery of Novel 3-Chymotrypsin-Like Protease Nonpeptidomimetic Hits

Clinical Snapshot

Key Findings

• P Value: Not reported for primary outcomes

• Effect Size: Lead compound LabMol-499: IC50 = 13.71 µM, Ki = 21.74 µM

• Primary Outcome: Identification of six promising 3CLpro inhibitors with IC50 ≤80 µM

• Nnt Or Sensitivity: Computational validation: AUC = 87%, Enrichment Factor = 7, BEDROC = 60-62%

• Confidence Interval: Not reported for primary outcomes

Clinical Application

Early-stage discovery requiring extensive development including optimization, safety studies, and clinical trials Relevant to Australian COVID-19 management strategies; would require TGA approval pathway for novel therapeutics. Complements existing PBS-listed antivirals (nirmatrelvir/ritonavir) Patients with COVID-19 requiring antiviral therapy, particularly those with resistance to current therapies

Abstract

The SARS-CoV-2 3-chymotrypsin-like (3CLpro) protease is a key target for the development of COVID-19 therapeutics. While ensitrelvir and nirmatrelvir are approved drugs for treatment, the continuous research and development for new antiviral drugs is necessary to combat the emergence of variants and other related viruses. This study employed structure- and ligand-based computer-assisted approaches to identify new 3CLpro nonpeptidomimetic inhibitors. Using data from COVID Moonshot, NCATS, and the literature, computational methods such as shape-based, ensemble docking, and machine learning (ML) techniques were developed, achieving robust validation metrics: AUC = 87%, EF = 7, BEDROC = 60% for shape-based; AUC = 87%, EF = 7.03, BEDROC = 62% for ensemble docking, and ACC = 81%, MCC = 62% for ML models, combing Random forest + ECFP4 fingerprint. These models were utilized in virtual screening (VS) campaigns using the H3D and ChemBridge libraries, from which six promising hits with IC50 values ≤80 µM were identified, including LabMol-499 with an IC50 of 13.71 µM and a Ki of 21.74 µM. Moreover, we found that LabMol-499 acts as a noncompetitive, reversible inhibitor of 3CLpro. These findings provide a foundation for hit-to-lead optimization of new nonpeptidomimetic 3CLpro inhibitors.

References

1. 1.Silva-Mendonça, S., Seanego, D., Jurisch, C., Mottin, M., Nader Motta, F., S A Rodrigues, B., S M Junior, G., Dos Santos Carvalho, A. M., Muniz de Oliveira, F., Sigurdardóttir, S., Sunnerhagen, P., Marques Dourado Bastos, I., Gessner, R., Chibale, K., & Horta Andrade, C. (2026). Structure- and ligand-based discovery of novel 3-chymotrypsin-like protease nonpeptidomimetic hits. ChemMedChem. https://doi.org/10.1038/srep42717