Work

Discovery of two novel small-molecule series with potent SARS-CoV-2 inhibition via putative nsp13 open-state trapping

Year: 2026

Type: article

Abstract: ) assays. We used a funnel-like computational framework where candidate compounds were progressively prioritized through different scores, improving robustness against the limitations of individual metrics. However, none of the docking-based scoring metrics, including MM/GBSA and Glide scores, showed statistically significant correlation with experimental activity, illustrating the limitations of docking-only approaches and supporting a major contribution of the machine-learning predictions to the high hit-identification rate. Although direct target validation is still lacking, the machine-learning (ML) workflow was grounded in experimental nsp13 inhibition labels, and molecular dynamics (MD) simulations suggest that these compounds can act by stabilizing apo-like open conformations of nsp13, with differential interactions involving the 1B domain contributing to potency differences. Among the compounds evaluated, the phenoxypropanol (PP) and bipiperidine (BPP) series stood out as the most promising SARS-CoV-2 antivirals. Integrated analysis of structure-activity relationships, physicochemical parameters, metabolic stability, and interdomain dynamics delineated structural optimization paths for both series.

Source: Chemical Science

DOI: 10.1039/d6sc02048h

Authors: Alma C. Castañeda-Leautaud, Thomas D. Bannister, Eunjung Kim, Donghoon Chung, Rommie E. Amaro

Institutions: University of California San Diego, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Louisville

Language: English

Topic: Computational Drug Discovery Methods

Subfield: Computational Theory and Mathematics

Field: Computer Science

Domain: Physical Sciences

SDG: Good health and well-being

Open Access status: diamond

Funders: Access Fund, Comisión México-Estados Unidos para el Intercambio Educativo y Cultural, National Institute of Allergy and Infectious Diseases