title: Exploring the binding sites of Staphylococcus aureus phenylalanine tRNA synthetase: A homology model approach.
abstract: Increased resistance of MRSA (multidrug resistance Staphylococcus aureus) to anti-infective drugs is a threat to global health necessitating the development of anti-infectives with novel mechanisms of action. Phenylalanine tRNA synthetase (PheRS) is a unique enzyme of the aminoacyl-tRNA synthetases (aaRSs), which are essential enzymes for protein biosynthesis. PheRS is an (αb)2tetrameric enzyme composed of two alpha subunits (PheS) and two larger beta subunits (PheT). Our potential target in the drug development for the treatment of MRSA infections is the phenylalanine tRNA synthetase alpha subunit that contains the binding site for the natural substrate. There is no crystal structure available for S. aureus PheRS, therefore comparative structure modeling is required to establish a putative 3D structure for the required enzyme enabling development of new inhibitors with greater selectivity. The S. aureus PheRS alpha subunit homology model was constructed using Molecular Operating Environment (MOE) software. Staphylococcus haemolyticus PheRS was the main template while Thermus thermophilus PheRS was utilised to predict the enzyme binding with tRNAphe. The model has been evaluated and compared with the main template through Ramachandran plots, Verify 3D and Protein Statistical Analysis (ProSA). The query protein active site was predicted from its sequence using a conservation analysis tool. Docking suitable ligands using MOE into the constructed model were used to assess the predicted active sites. The docked ligands involved the PheRS natural substrate (phenylalanine), phenylalanyl-adenylate and several described S. aureus PheRS inhibitors.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, United Kingdom; Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig P.C. 44519, Egypt.
authors.forename: Samar S
authors.initials: SS
authors.lastname: Elbaramawi
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig P.C. 44519, Egypt.
authors.forename: Samy M
authors.initials: SM
authors.lastname: Ibrahim
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig P.C. 44519, Egypt.
authors.forename: El-Sayed M
authors.initials: EM
authors.lastname: Lashine
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig P.C. 44519, Egypt.
authors.forename: Mohamed E
authors.initials: ME
authors.lastname: El-Sadek
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, United Kingdom.
authors.forename: Efi
authors.initials: E
authors.lastname: Mantzourani
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, United Kingdom. Electronic address: simonsc@cardiff.ac.uk.
authors.forename: Claire
authors.initials: C
authors.lastname: Simons
mesh_terms: D000595:Amino Acid Sequence; D000926:Anticodon / Q000235:genetics; D001665:Binding Sites; D008670:Metals / Q000378:metabolism; D062105:Molecular Docking Simulation; D009690:Nucleic Acid Conformation; D010652:Phenylalanine-tRNA Ligase / Q000737:chemistry*; D010802:Phylogeny; D021122:Protein Subunits / Q000378:metabolism; D012360:RNA, Transfer, Phe / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D013211:Staphylococcus aureus / Q000201:enzymology*; D040681:Structural Homology, Protein; D016963:Thermus thermophilus / Q000201:enzymology
chemical_list: D000926:Anticodon; D008670:Metals; D021122:Protein Subunits; D012360:RNA, Transfer, Phe; D010652:Phenylalanine-tRNA Ligase
keywords: Aminoacyl tRNA synthetase; Binding site interactions; Computational analysis; MRSA; Molecular docking