A homology model for Clostridium difficile methionyl tRNA synthetase: active site analysis and docking interactions.
Treatment of C. difficile infection is one of the most difficult biomedical challenges. To develop novel antibacterials, researchers have been targeting bacterial molecular functions that are essential for its growth. The methionyl tRNA synthetase (MetRS) is strictly required for protein biosynthesis and success was reported in developing antibacterials to inhibit this enzyme. The present study was aimed at building and analyzing a homology model for C. difficile MetRS in the context of drug design. A homology model of C. difficile MetRS was constructed using Molecular Operating Environment (MOE) software. A. aeolicus MetRS was the main template while the query zinc binding domain was modeled using T. thermophilus MetRS. The model has been assessed and compared to its main template (Ramachandran, ERRAT and ProSA). The active site of the query protein has been predicted from its sequence using a detailed conservation analysis (ClustalW2). Using MOE software, suitable ligands were docked in the constructed model, including a C. difficile MetRS inhibitor REP3123 and the enzyme natural substrate, and the key active site residues and interactions were identified. These docking studies have validated the active site conformation in the constructed model and identified binding interactions.
Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF03NB, UK.
Ehab
E
Al-Moubarak
Claire
C
Simons
D000595:Amino Acid Sequence; D001483:Base Sequence; D020134:Catalytic Domain / Q000502:physiology*; D016360:Clostridioides difficile / Q000737:chemistry* / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000737:chemistry; D008718:Methionine-tRNA Ligase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010802:Phylogeny; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D012358:RNA, Transfer, Met / Q000737:chemistry; D015203:Reproducibility of Results; D016415:Sequence Alignment; D015032:Zinc / Q000737:chemistry
D004791:Enzyme Inhibitors; D012358:RNA, Transfer, Met; D008718:Methionine-tRNA Ligase; D015032:Zinc