What question did this study set out to answer?

The aim is to discover broad-spectrum antiviral inhibitors targeting the conserved nucleocapsid protein of coronaviruses via structural-based screening.

March 1, 2026Open Access

Broad-Spectrum Inhibitor Discovery Targeting Coronavirus Nucleocapsid Proteins via 3D Structure-Based Virtual Screening and Molecular Dynamics

Key Points

The aim is to discover broad-spectrum antiviral inhibitors targeting the conserved nucleocapsid protein of coronaviruses via structural-based screening.
Performed 3D structure-based virtual screening of 494 compounds using AutoDock Vina.
Evaluated interactions with the N-terminal RNA-binding domain and C-terminal dimerization domains of various coronaviruses.
Conducted ADME profiling and 100 ns molecular dynamics simulations using GROMACS.
Myricetin displayed the highest docking scores across multiple targets, indicating strong binding.
Curcumin showed moderate binding affinity, with varied stability in molecular dynamics simulations.
MCC950 met drug-likeness criteria and demonstrated promising interactions, warranting further investigation.

Abstract

Rapid antigenic drift in the coronavirus spike protein motivates alternative antiviral strategies. We target the conserved nucleocapsid (N) protein—central to RNA binding, genome packaging, and replication—and perform a comparative, cross-species 3D structure-based in silico evaluation. A library of 494 compounds (natural, phytochemical, synthetic) was docked with AutoDock Vina against the MERS-CoV N–terminal RNA–binding domain (NTD; PDB 7DYD) and the C–terminal dimerization domains (CTD) of SARS-CoV (2CJR) and SARS-CoV-2 (8R6E), reflecting the availability of high-resolution, functionally relevant domain structures for each virus. Top-ranked poses underwent ADME profiling and 100 ns GROMACS molecular-dynamics (MD) simulations. Myricetin 3-O-β-D-Galactopyranoside (myricetin) showed the most favorable predicted docking scores across targets (−8.9 kcal/mol, MERS–NTD; −10.1, SARS–CTD; −9.8, SARS-CoV-2 CTD). Curcumin showed moderate predicted affinity (−7.1 to −8.1), while MCC950 achieved consistently favorable docking score (−7.9 to −9.0). ADME results highlighted a trade-off: glycosylated flavonoids offered rich interaction networks but violated oral drug-likeness criteria (e.g., high TPSA), whereas MCC950 met Lipinski/Veber guidelines, supporting translational potential. MD analyses revealed ligand- and target-specific stability: myricetin maintained persistent binding over 100 ns in the SARS-CoV-2 CTD with lower RMSD than comparators; curcumin exhibited transient stability (~30 ns) in MERS- and SARS-bound complexes; MCC950 showed intermittent interactions. Collectively, these findings suggest that the conserved N protein RNA-binding groove represents a resistance-resilient target for broad-spectrum antiviral discovery. Natural flavonoids provide promising scaffolds for optimization, and MCC950 warrants further exploration given its drug-like profile. As this study is purely computational, the results are hypothesis-generating and should be validated via RNA-binding disruption assays, antiviral cell studies, and in vivo models.

Broad-Spectrum Inhibitor Discovery Targeting Coronavirus Nucleocapsid Proteins via 3D Structure-Based Virtual Screening and Molecular Dynamics

Key Points

Abstract

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