Computational guided identification of novel potent inhibitors of N-terminal domain of nucleocapsid protein of severe acute respiratory syndrome coronavirus 2

Abstract

The Coronavirus Disease 2019, caused by the severe acute respiratory syndrome coronavirus 2 is an exceptionally contagious disease that leads to global epidemics with elevated mortality and morbidity. There are currently no efficacious drugs targeting coronavirus disease 2019, therefore, it is an urgent requirement for the development of drugs to control this emerging disease. Owing to the importance of nucleocapsid protein, the present study focuses on targeting the N-terminal domain of nucleocapsid protein from severe acute respiratory syndrome coronavirus 2 to identify the potential compounds by computational approaches such as pharmacophore modeling, virtual screening, docking and molecular dynamics. We found three molecules (ZINC000257324845, ZINC000005169973 and ZINC000009913056), which adopted a similar conformation as guanosine monophosphate (GMP) within the N-terminal domain active site and exhibiting high binding affinity (>À8.0 kcalmol À1). All the identified compounds were stabilized by hydrogen bonding with Arg107, Tyr111 and Arg149 of Nterminal domain. Additionally, the aromatic ring of lead molecules formed p interactions with Tyr109 of N-terminal domain. Molecular dynamics and Molecular mechanic/Poisson-Boltzmann surface area results revealed that N-terminal domainligand(s) complexes are less dynamic and more stable than N-terminal domain-GMP complex. As the identified compounds share the same corresponding pharmacophore properties, therefore, the present results may serve as a potential lead for the development of inhibitors against severe acute respiratory syndrome coronavirus 2.

Multivalent binding of the partially disordered SARS-CoV-2 nucleocapsid phosphoprotein dimer to RNA

“…The FL-N dimerization and multivalent RNA binding is critical for the viral life cycle and could inform potential drug therapy because both the NTD (6,7,47,48) and CTD (49) are potential drug targets. Therefore, developing compounds that either disrupt the RNA binding or dimerization requires understanding of not only how these compounds interfere with the individual domains but with the larger protein/RNA complexes involving many FL-N copies and longer RNA (6)(7)(8).…”

Drug-Repurposing Approach To Combat Staphylococcus aureus: Biomolecular and Binding Interaction Study

“…Molecular dynamics for FmtA–Native and FmtA–inhibitor(s) complexes were carried out using GROMACS software package, as performed by Dalal et al The protein coordinates and topology files were created utilizing the GROMOS96 43a1 force field, and the protonation states were updated at pH 7.2 by the H ++ server. ,− The ligands (gemifloxacin, paromomycin, streptomycin, and tobramycin) were prepared using PRODRG (), and the charges were corrected by the 6-311G (d,p) basis set of DFT/B3LYP in Gaussian. − The systems were neutralized by substituting the counterions (Cl – ) and solvated in triclinic boxes (Table S1). The systems were equilibrated for 1 ns and minimized for 50,000 steps, as done by Dalal et al The molecular dynamics simulation was run for 100 ns for all the systems, and the files were updated every 10 ps to evaluate the root-mean-square fluctuations (RMSF), root-mean-square deviation (RMSD), hydrogen-bond numbers, radius of gyration (Rg), and solvent-accessible surface area (SASA). , …”

“…Molecular dynamics for FmtA–Native and FmtA–inhibitor(s) complexes were carried out using GROMACS software package, as performed by Dalal et al 26 The protein coordinates and topology files were created utilizing the GROMOS96 43a1 force field, and the protonation states were updated at pH 7.2 by the H ++ server. 26 , 35 − 38 The ligands (gemifloxacin, paromomycin, streptomycin, and tobramycin) were prepared using PRODRG ( ), and the charges were corrected by the 6-311G (d,p) basis set of DFT/B3LYP in Gaussian. 39 − 42 The systems were neutralized by substituting the counterions (Cl – ) and solvated in triclinic boxes ( Table S1 ).…”

Plant-Derived Antimicrobial Peptides Are Effective in Combating the Pathogenicity of SARS-CoV-2, a Novel Therapeutic Approach

“…HADDOCK webserver employs a data-driven approach to perform the ab initio docking process without experimental constraints. It considers diverse information, such as shape data from cryo-electron microscopy experiments, X-ray scattering, etc [17]. Haddock web server is majorly used in the Critical Assessment of Protein Interaction (CAPRI) experiments.…”