Computational screening of plant-derived compounds against SARS-CoV-2: methodological trends, limitations, and opportunities
Alejandra Ojeda-Pérez, Rocío Borges-Argaez, Norberto Sánchez‐Cruz · Frontiers in Drug Discovery · 2026
The SARS-CoV-2 pandemic triggered extensive in silico screening efforts exploiting the structural diversity of plant-derived secondary metabolites. Although numerous studies proposed natural products as potential inhibitors, substantial variability in methodological design and validation criteria have complicated the translational reliability of many reported predictions. This work critically examines recent computational workflows targeting SARS-CoV-2, shifting the focus from individual compounds to methodological trends and recurrent limitations. We analyze how molecular docking, molecular dynamics simulations, binding free energy calculations, and pharmacokinetic filtering are implemented across different studies, emphasizing sources of bias, validation practices, and target-specific challenges. By identifying recurring strengths and limitations, we assess the robustness and interpretability of computational outputs. Overall, this work highlights the importance of rigorous validation and critical interpretation for improving the translational relevance of virtual screening predictions involving plant-derived compounds.