An insight into the simulation directed understanding of the mechanism in SARS CoV-2 N-CTD, dimer integrity, and RNA-binding: Identifying potential antiviral inhibitors. Issue 24 (26th December 2022)

• Record Type: Journal Article
• Authors: Chauhan, Arushi; Avti, Pramod K.; Shekhar, Nishant; Prajapat, Manisha; Sarma, Phulen; Sangwan, Namrata; Singh, Jitender; Bhattacharyya, Anusuya; Kumar, Subodh; Kaur, Hardeep; Sharma, Saurabh; Prakash, Ajay; Medhi, Bikash
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 40:Issue 24(2022)
• Page Start: 13912
• Page End: 13924
• Publication Date: 2022-12-26
• Subjects: Dimer structural integrity -- molecular dynamics simulations (MD) -- nucleocapsid C terminal domain -- radius of gyration (Rgyr) -- severe acute respiratory syndrome coronavirus 2 (SARS CoV-2); Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2021.1996463
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract: Coronavirus 2019 is a transmissible disease and has caused havoc throughout the world. The present study identifies the novel potential antiviral inhibitors against the nucleocapsid C-terminal domain that aids in RNA-binding and replication. A total of 485, 629 compounds were screened, and MD was performed. The trajectory analysis (DCCM & PCA), structural integrity, and degree of compaction depicted the protein-ligand complex stability (PDB-PISA and Rgyr ). Results obtained from screening shortlists 13 compounds possessing high Docking score. Further, seven compounds had a permissible RMSD limit (3 Å), with robust RMSF. Post-MD analysis of the top two compounds (204 and 502), DCCM & PCA analysis show a positive atomic displacements correlation among residues of active sites-dimer (Chain A and Chain B) & residual clustering. The ΔGint of RNA-bound (-83.5 kcal/mol) and drug-bound N-CTD-204 (-40.8 kcal/mol) and 502(-39.7 kcal/mol) as compared to Apo (-35.95 kcal/mol) suggests stabilization of protein, with less RNA-binding possibility. The Rgyr values depict the loss of compactness on RNA-binding when compared to the drug-bound N-CTD complex. Further, overlapping the protein complexes (0 ns and 100 ns) display significant changes in RMSD of the protein (204-2.07 Å and 502-1.89 Å) as compared to the Apo (1.72 Å) and RNA-bound form (1.76 Å), suggesting strong interaction for compound 204 as compared to 502. ADMET profiling indicates that these compounds can be used for further experiments ( in vitro and pre-clinical). Compound 204 could be a promising candidate for targeting the N-protein-RNA assembly and viral replication. Graphical abstract: UF0001 Communicated by Ramaswamy H. Sarma