Abstract
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.
Highlights
The adoption of a brisk and cost-effective methodology in the discovery of new drug leads has caused pharmaceutical companies to re-evaluate R&D strategies
There is a significant demand for human norovirus agents, which can curtail the therapy period, displaying excellent cell membrane permeability and minimal or no side effects
CMX521 is theCalculations first nucleoside analog that has moved to clinical trials to prevent and treat huHigh Throughput man norovirus
Summary
The adoption of a brisk and cost-effective methodology in the discovery of new drug leads has caused pharmaceutical companies to re-evaluate R&D strategies. A computer-aided drug design (CADD) approach, which uses substantial computational power, has become one of the more efficient searches for new lead compounds [1] This approach includes identifying hit compounds using structure or ligand-based virtual screening and in silico simulations, chemical and biological information about ligands and molecular targets of feasible hits. We used high throughput virtual screening (HTVS), combined with epharmacophore screening and molecular dynamics studies, to efficiently and inexpensively search for new lead compounds that could potentially combat the human norovirus. These methodologies have underlined compounds that are structurally similar to the CMX521 molecule, which can be lead to drug design and development against the HuNoV.
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