“…The protein-ligand binding energies of the FmtA conf -WTA and vFmtA conf -WTA complexes were determined by MM-GBSA, as done by Dalal et al , Binding free energy calculations were performed from the averages of 2000 snapshots retrieved every 10 ps from the last 20 ns (80–100 ns) of the MD simulation. This method has been utilized as a reliable tool for the determination of the binding free energy (Δ G mmgbsa ) using the following equation:…”
FmtA is a novel esterase that shares the penicillinbinding protein (PBP) core structural folding but found to hydrolyze the removal of D-Ala from teichoic acids. Molecular docking, dynamics, and MM-GBSA of FmtA and its variants S127A, K130A, Y211A, D213A, and K130AY211A, in the presence or absence of wall teichoic acid (WTA), suggest that active site residues S127, K130, Y211, D213, N343, and G344 play a role in substrate binding. Quantum mechanics (QM)/molecular mechanics (MM) calculations reveal that during WTA catalysis, K130 deprotonates S127, and the nucleophilic S127 attacks the carbonyl carbon of D-Ala bound to WTA. The tetrahedral intermediate (TI) complex is stabilized by hydrogen bonding to the oxyanion holes. The TI complex displays a high energy gap and collapses to an energetically favorable acyl-enzyme complex.
“…The protein-ligand binding energies of the FmtA conf -WTA and vFmtA conf -WTA complexes were determined by MM-GBSA, as done by Dalal et al , Binding free energy calculations were performed from the averages of 2000 snapshots retrieved every 10 ps from the last 20 ns (80–100 ns) of the MD simulation. This method has been utilized as a reliable tool for the determination of the binding free energy (Δ G mmgbsa ) using the following equation:…”
FmtA is a novel esterase that shares the penicillinbinding protein (PBP) core structural folding but found to hydrolyze the removal of D-Ala from teichoic acids. Molecular docking, dynamics, and MM-GBSA of FmtA and its variants S127A, K130A, Y211A, D213A, and K130AY211A, in the presence or absence of wall teichoic acid (WTA), suggest that active site residues S127, K130, Y211, D213, N343, and G344 play a role in substrate binding. Quantum mechanics (QM)/molecular mechanics (MM) calculations reveal that during WTA catalysis, K130 deprotonates S127, and the nucleophilic S127 attacks the carbonyl carbon of D-Ala bound to WTA. The tetrahedral intermediate (TI) complex is stabilized by hydrogen bonding to the oxyanion holes. The TI complex displays a high energy gap and collapses to an energetically favorable acyl-enzyme complex.
“…The crystal structure of FmtA (PDB ID: 5ZH8) was considered as a protein receptor to screen potential compounds . The virtual screening of FmtA against 1930 drugs of e-LEA3D: Cheminformatics Tools and Database () was performed utilizing AutoDock Vina in PyRx, as done by Dalal et al − The best drug molecules with higher binding energies were re-docked by utilizing HADDOCK () and AutoDockTools. ,− The molecular grid in virtual screening and molecular docking was set around the active site residues (Ser127, Lys130, Tyr211, and Asp213) of FmtA. The generated docking conformations were evaluated, and figures were made in Maestro and PyMOL. − …”
Section: Methodsmentioning
confidence: 99%
“…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). , …”
Staphylococcus aureus is
considered
as one of the most widespread bacterial pathogens and continues to
be a prevalent cause of mortality and morbidity across the globe.
FmtA is a key factor linked with methicillin resistance in S. aureus. Consequently, new antibacterial compounds
are crucial to combat S. aureus resistance.
Here, we present the virtual screening of a set of compounds against
the available crystal structure of FmtA. The findings indicate that
gemifloxacin, paromomycin, streptomycin, and tobramycin were the top-ranked
potential drug molecules based on the binding affinity. Furthermore,
these drug molecules were analyzed with molecular dynamics simulations,
which showed that the identified molecules formed highly stable FmtA–inhibitor(s)
complexes. Molecular mechanics Poisson–Boltzmann surface area
and quantum mechanics/molecular mechanics calculations suggested that
the active site residues (Ser127, Lys130, Tyr211, and Asp213) of FmtA
are crucial for the interaction with the inhibitor(s) to form stable
protein–inhibitor(s) complexes. Moreover, fluorescence- and
isothermal calorimetry-based binding studies showed that all the molecules
possess dissociation constant values in the micromolar scale, revealing
a strong binding affinity with FmtAΔ80, leading to
stable protein–drug(s) complexes. The findings of this study
present potential beginning points for the rational development of
advanced, safe, and efficacious antibacterial agents targeting FmtA.
“…Various frontier molecular orbitals like highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) as well the optimized geometry for (1–5) were determined in gaseous and water to understand the localization of the electron density to known about nucleophilic and electrophilic sites ( Fig. 1 ) [ [38] , [39] , [40] , [41] ]. Fig.…”
The new coronavirus is trying the kill the humanity with its infectious nature and its first infection was reported in 2019; named as COVID-19. Health-care systems are using repurposing drugs to cure the patients from this infection. Remdesivir found to have good potential against the infection and is being extensively used during the 1st and 2nd wave of COVID-19. Therefore, in the present work, authors have studied the interaction of remdesivir with different ionic liquids with change in cations using density functional theory calculation in gaseous and water. Based on the DFT calculations, it was found that remdesivir interacts with different ionic liquids effectively based on the energy; further, the change in free energy for Remdesivir-[Bet-ester][Lev] was found to be satisfactory as −3223.5758 and −3223.6533 hartree per particle in default and water respectively but more than Remdesivir-[Chol][Lev]. Further, the potential of remdesivir with and without ionic liquids against the main protease of SARS-CoV-2 was investigated using molecular docking. Results revealed that Remdesivir-[Chol][Lev] and Remdesivir-[Chol-ester][Lev] have shown the promising results with binding energy of −129.64 kcal/mol and −125.44 kcal/mol respectively. It is important to mention that changing the cations in ionic liquid play an important role in the docking. It is also observed that the ionic liquid having sodium as cation then the binding energy against Mpro of CoV is poor and even less than the remdesivir alone.
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