Phenylalanyl tRNA synthetase (PheRS) substrate mimics: design, synthesis, molecular dynamics and antimicrobial evaluation

Noureldin, Nada A.; Richards, Jennifer; Kothayer, Hend; Baraka, Mohammed M.; El-Adl, Sobhy M.; Wootton, Mandy; Simons, Claire

doi:10.1039/d1ra06439h

Cited by 5 publications

(3 citation statements)

References 25 publications

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“…Docking and molecular dynamics simulations were performed as previously described [ 75 , 76 ]. Docking studies, using the constructed model, were performed to generate protein–ligand complexes, using MOE [ 28 ] until a RMSD gradient of 0.01 kcal mol −1 Å −1 with the MMFF94 forcefield (ligands) and partial charges were automatically calculated.…”

Section: Methodsmentioning

confidence: 99%

Exploring Proteus mirabilis Methionine tRNA Synthetase Active Site: Homology Model Construction, Molecular Dynamics, Pharmacophore and Docking Validation

Elbaramawi,

Eissa,

Noureldin

et al. 2023

Pharmaceuticals

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Currently, the treatment of Proteus mirabilis infections is considered to be complicated as the organism has become resistant to numerous antibiotic classes. Therefore, new inhibitors should be developed, targeting bacterial molecular functions. Methionine tRNA synthetase (MetRS), a member of the aminoacyl-tRNA synthetase family, is essential for protein biosynthesis offering a promising target for novel antibiotics discovery. In the context of computer-aided drug design (CADD), the current research presents the construction and analysis of a comparative homology model for P. mirabilis MetRS, enabling development of novel inhibitors with greater selectivity. Molecular Operating Environment (MOE) software was used to build a homology model for P. mirabilis MetRS using Escherichia coli MetRS as a template. The model was evaluated, and the active site of the target protein predicted from its sequence using conservation analysis. Molecular dynamic simulations were performed to evaluate the stability of the modeled protein structure. In order to evaluate the predicted active site interactions, methionine (the natural substrate of MetRS) and several inhibitors of bacterial MetRS were docked into the constructed model using MOE. After validation of the model, pharmacophore-based virtual screening for a systemically prepared dataset of compounds was performed to prove the feasibility of the proposed model, identifying possible parent compounds for further development of MetRS inhibitors against P. mirabilis.

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Section: Methodsmentioning

confidence: 99%

Exploring Proteus mirabilis Methionine tRNA Synthetase Active Site: Homology Model Construction, Molecular Dynamics, Pharmacophore and Docking Validation

Elbaramawi,

Eissa,

Noureldin

et al. 2023

Pharmaceuticals

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“…Molecular docking and molecular dynamics simulations were performed as previously described. 25,26 Briefly docking studies, using the crystal structure of Mtb CYP121A1 co-crystallised with cYY (pdb 4 ) were performed to generate PDB Mtb CYP121A1–ligand complexes, using MOE 22 until a RMSD gradient of 0.01 kcal mol −1 Å −1 with the MMFF94 forcefield (ligands) and partial charges were automatically calculated. The charge of the haem iron at physiological pH was set to 3 + (geometry d 2 sp 3 ) through the atom manager in MOE.…”

Section: Methodsmentioning

confidence: 99%

Synthesis, biological evaluation and computational studies of pyrazole derivatives as Mycobacterium tuberculosis CYP121A1 inhibitors

et al. 2022

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“…The parameters such as bond angles and bond lengths generated after optimization is given in Table S1. Based on the Periodic Bond Chain (PBC) crystal data, it is revealed that compound TC is orthorhombic [34] having space group P222 1 and cell dimensions; a = 16.7237 Å, b = 11.1801 Å and c = 8.8999 Å having α = β = γ = 90°.…”

Section: Molecular Geometrymentioning

confidence: 99%

Theoretical Study of Azetidine Derivative by Quantum Chemical Methods, Molecular Docking and Molecular Dynamic Simulations

Sinha

Yadav

2023

ChemistrySelect

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Azetidine substituent group has a wide range of application in organic chemistry and medical field. In this study, a novel azetidine derivative and its reaction mechanism has been reported. Using quantum chemical method spectroscopic analysis and other parameters such as electronic and thermodynamic properties were studied to understand the physical as well as chemical behavior of the reported compound. Additionally, to study the antiviral activity, molecular docking studies were carried out against Hepatitis virus C (HCV) NS5B genotype and Norovirus as target protein. In order to validate the docking results molecular dynamic (MD) simulation and Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) were calculated at 90 ns. The RMSD was obtained within the range 0.75 Å to 1.5 Å and binding energies (ΔG bind ) for the two complexes was found to be À 18.34 kJ/mol and À 16.10 kJ/ mol for each respective targets.It was found that reported compound can act as potential inhibitor for HCVand Norovirus.

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Phenylalanyl tRNA synthetase (PheRS) substrate mimics: design, synthesis, molecular dynamics and antimicrobial evaluation

Abstract: Nineteen novel compounds were designed to mimic Phe-AMP, as a new hope to find novel antibacterial agents and combat the antibiotic resistance. E. faecalis PheS homology model was constructed to study the mimics–enzyme interactions in more detail.

Cited by 5 publications

References 25 publications

Exploring Proteus mirabilis Methionine tRNA Synthetase Active Site: Homology Model Construction, Molecular Dynamics, Pharmacophore and Docking Validation

Exploring Proteus mirabilis Methionine tRNA Synthetase Active Site: Homology Model Construction, Molecular Dynamics, Pharmacophore and Docking Validation

Synthesis, biological evaluation and computational studies of pyrazole derivatives as Mycobacterium tuberculosis CYP121A1 inhibitors

Theoretical Study of Azetidine Derivative by Quantum Chemical Methods, Molecular Docking and Molecular Dynamic Simulations

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