Key result
CID-57930781 and CID-44396095 form stable MNV-RdRp complexes in simulations, showing potential as human norovirus inhibitors.
Why the study?
Norovirus RNA-dependent RNA polymerase is vital for viral genome replication and transcription, making it a critical target for novel anti-norovirus agents.
Compounds CID-57930781 and CID-44396095 were identified as potential inhibitors of human norovirus RNA-dependent RNA polymerase through virtual screening and molecular dynamics simulations.
May inform norovirus RdRp inhibitor discovery; leaves open clinical utility pending in vitro and in vivo validation.
Noroviruses are non-enveloped viruses with a positive-sense single-stranded RNA (ssRNA) genome belonging to the genus Norovirus, from the family Caliciviridae, which are accountable for acute gastroenteritis in humans. The Norovirus genus is subdivided into seven genogroups, i.e., (GI-GVII); among these, the genogroup II and genotype 4 (GII.4) strains caused global outbreaks of human norovirus (HuNov) disease. The viral genome comprises three open reading frames (ORFs). ORF1 encodes the nonstructural polyprotein that is cleaved into six nonstructural proteins, which include 3C-like cysteine protease (3CLpro) and a viral RNA-dependent RNA polymerase. ORF2 and ORF3 encode the proteins VP1 and VP2. The RNA-dependent RNA polymerase (RdRp) from noroviruses is one of the multipurpose enzymes of RNA viruses vital for replicating and transcribing the viral genome, making the virally encoded enzyme one of the critical targets for the development of novel anti-norovirus agents. In the quest for a new antiviral agent that could combat HuNov, high throughput virtual screening (HTVS), combined with e-pharmacophore screening, was applied to screen compounds from the PubChem database. CMX521 molecule was selected as a prototype for a similarity search in the PubChem online database. Molecular dynamics simulations were employed to identify different compounds that may inhibit HuNov. The results predicted that compound CID-57930781 and CID-44396095 formed stable complexes with MNV-RdRp within 50 ns; hence, they may signify as promising human norovirus inhibitors.
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Ebenezer et al. (2020) studied Human norovirus (HuNov) disease. Compounds CID-57930781 and CID-44396095 was evaluated on Stable complex formation with MNV-RdRp. Compounds CID-57930781 and CID-44396095 formed stable complexes with MNV-RdRp within 50 ns in molecular dynamics simulations, indicating potential as human norovirus inhibitors.
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