Virtual screening and dynamics of potential inhibitors targeting RNA binding domain of nucleocapsid phosphoprotein from SARS-CoV-2.

The emergence of the coronavirus disease-2019 pandemic has led to an outbreak in the world. The SARS-CoV-2 is seventh and latest in coronavirus family with unique exonucleases for repairing any mismatches in newly transcribed genetic material. Therefore, drugs with novel additional mechanisms are required to simultaneously target and eliminate the virus. Thus, a newly deciphered N protein is taken as a target that belongs to SARS-CoV-2. They play a vital role in RNA transcription, viral replication and new virion formation. This study used virtual screening, molecular modeling and docking of the 8987 ligands from Asinex and PubChem databases against this novel target protein. Three hotspot sites having DScore ≥1 (Site 1, Site 2 and Site 3) for ligand binding were selected. Subsequently, high throughput screening, standard precision and extra precision docking process and molecular dynamics concluded three best drugs from two libraries. Two antiviral moieties from Asinex databases (5817 and 6799) have docking scores of -10.29 and -10.156; along with their respective free binding energies (Δ bind) of -51.96 and -64.36 on Site 3. The third drug, Zidovudine, is from PubChem database with docking scores of -9.75 with its binding free energies (Δ bind) of -59.43 on Site 3. The RMSD and RMSF were calculated for all the three drugs through molecular dynamics simulation studies for 50 ns. Zidovudine shows a very stable interaction with fluctuation starting at 2.4 Å on 2 ns and remained stable at 3 Å from 13 to 50 ns. Thus, paving the way for further biological validation as a potential treatment.Communicated by Ramaswamy H. Sarma.