A panoptic uncovering of the dynamical evolution of the Zika Virus NS5 methyltransferase binding site loops—zeroing in on the molecular landscape

Abstract

The global threat of the Zika virus to humanity is real. Innovative and potent anti-Zika virus drugs are still at large, due to the lack of anti-Zika virus drugs that have passed phase 1 trials. Experimental research has revealed novel inhibitors of Zika virus NS5 methyltransferase enzyme. This study has taken a step further to provide insight into the molecular dynamics of Zika virus and inhibitor binding, which have not been established experimentally. Movements of the methyltransferase binding site loops have a large role to play in the methylation of the viral mRNA cap, which is essential for Zika virus replication. Here, we pinpoint the binding interactions between each potential inhibitor and the methyltransferase, residues that are responsible for binding, as well as which inhibitor-bound complex renders the methyltransferase more stable. We also highlight the conformational changes that occur within the methyltransferase to accommodate binding of inhibitors and consequences of those changes upon the RNA- and cap-binding sites in the methyltransferase. This research will improve the understanding of the Zika virus NS5 methyltransferase enzyme, and will be beneficial in driving the development of anti-Zika virus drugs.

A Novel Small Molecule Inhibitor of p38⍺ MAP Kinase Augments Cardiomyocyte Cell Cycle Entry in Response to Direct Cell Cycle Stimulation

“…Thermodynamic calculations provide quantitative mechanistic insights into the binding profile of p38⍺ MAP kinase inhibitors. The binding free energies of the SB203580, NDPPC, and NCT503 binding at the p38⍺ MAP kinase (N-terminal domain) site were calculated using the Molecular mechanics with the generalized Born/Poisson-Boltzmann and surface area solvation (MM/PBSA) method provided in the AMBER14 package (Devnarain & Soliman, 2018;Genheden & Ryde, 2015). Our MM/PBSA calculations showed that the compounds exhibited considerably favorable negative energies, indicating strong and high-affinity binding (Table 1).…”

“…The integrated CPPTRAJ and PTRJ modules implemented in AMBER18 were used to generate the output coordinates and printed trajectories (Roe & Cheatham, 2013). The visual analysis of structures was performed using combined graphical interfaces of the UCSF Chimera (Yang et al, 2012), Molegro Molecular Viewer (Devnarain & Soliman, 2018), and BIOVIA Discovery Studio (A. T. Adewumi et al, 2022). Lastly, the data were processed with MicroCal Origin-6.0 data software (Seifert, 2014).…”

Weak spots inhibition in the Mycobacterium tuberculosis antigen 85C target for antitubercular drug design through selective irreversible covalent inhibitor-SER124

“…It is an imperative method used to determine the in-depth binding mechanism of the receptor-ligand interacting systems. Here, we used the BFE with the MM/GBS technique to estimate the binding affinity within the docked Ag85C-CyC 8b system to gain insights into their binding landscape (Devnarain & Soliman, 2018). Thus, we employed this approach to calculate the binding free energies of the inhibitor CyC 8b modelled in the open conformation using 35,000 snapshots generated from the 350 ns trajectories.…”

Identification of a Potential Zika Virus Inhibitor Targeting NS5 Methyltransferase Using Virtual Screening and Molecular Dynamics Simulations

“…This protein has two functional domains: an N -terminal, which possess methyltransferase (MTase) activity promoting RNA capping and a C -terminal with RNA polymerase (RdRp) activity . NS5MTase has four residues in the active site (Lys61–Asp146–Lys182–Glu218), which promotes the addition of methyl groups at N-7, 2′O positions of RNA and the 2′-O-ribose position of adenosines of RNA from an S-adenosyl- l -methionine (SAM) methyl (CH 3 ) group donor . Viral RNA methylation mechanisms differ from those of the host and have been reported as essential improvement genomic stability and evasion of the host’s innate immune system during the flaviviral replicative cycle. , …”

“…12 NS5MTase has four residues in the active site (Lys61−Asp146−Lys182−Glu218), which promotes the addition of methyl groups at N-7, 2′O positions of RNA and the 2′-O-ribose position of adenosines of RNA from an S-adenosyl-L-methionine (SAM) methyl (CH 3 ) group donor. 13 Viral RNA methylation mechanisms differ from those of the host and have been reported as essential improvement genomic stability and evasion of the host's innate immune system during the flaviviral replicative cycle. 14,15 Structure-based virtual screening (SBVS), molecular docking, dynamics simulation (DM), and QM/MM (quantum mechanics/molecular mechanics) have been used as tools for the identification of promising drugs.…”