In silico study and validation of phosphotransacetylase (PTA) as a putative drug target for Staphylococcus aureus by homology-based modelling and virtual screening.
Staphylococcus aureus, a Gram-positive bacterium, can cause a range of illnesses from minor skin infections to life-threatening diseases, such as bacteraemia, endocarditis, meningitis, osteomyelitis, pneumonia, toxic shock syndrome and sepsis. Due to the emergence of antibiotic resistance strains, there is a need to develop of new class of antibiotics or drug for this pathogen. The phosphotransacetylase enzyme plays an important role in the acetate metabolism and found to be essential for the survival of the S. aureus. This enzyme was evaluated as a putative drug target for S. aureus by in silico analysis. The 3D structure of the phosphotransacetylase from S. aureus was modelled, using the 1TD9 chain 'A' from Bacillus subtilis as a template at the resolution of 2.75 Å. The generated model has been validated by PROCHECK, WHAT IF and SuperPose. The docking was performed by the Molegro virtual docker using the ZINC database generated ligand library. The ligand library was generated within the limitation of the Lipinski rule of five. Based on the dock-score, five molecules have been subjected to ADME/TOX analysis and subjected for pharmacophore model generation. The zinc IDs of the potential inhibitors are ZINC08442078, ZINC8442200, ZINC 8442087 and ZINC 8442184 and found to be pharmacologically active antagonist of phosphotransacetylase. The molecules were evaluated as no-carcinogenic and persistent molecule by START programme.
National Research Laboratory of Bioactive Materials, Department of Biological Engineering, Inha University, Incheon 42-751, Korea. moryavviek@gmail.com
V K
VK
Morya
Varun
V
Dewaker
Eun-Ki
EK
Kim
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D019295:Computational Biology; D004353:Drug Evaluation, Preclinical; D004795:Enzyme Stability; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D010709:Phosphate Acetyltransferase / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D015203:Reproducibility of Results; D017386:Sequence Homology, Amino Acid; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology*; D013816:Thermodynamics; D014584:User-Computer Interface
D000900:Anti-Bacterial Agents; D010709:Phosphate Acetyltransferase