National Research Laboratory of Bioactive Materials, Department of Biological Engineering, Inha University, Incheon 42-751, Korea.
Appl Biochem Biotechnol. 2012 Dec;168(7):1792-805. doi: 10.1007/s12010-012-9897-z. Epub 2012 Oct 6.
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.
金黄色葡萄球菌是一种革兰氏阳性菌，可以引起从轻微皮肤感染到危及生命的疾病，如菌血症、心内膜炎、脑膜炎、骨髓炎、肺炎、中毒性休克综合征和败血症。由于抗生素耐药菌株的出现，需要开发针对这种病原体的新类别的抗生素或药物。磷酸转乙酰酶在乙酸代谢中起着重要作用，被发现对金黄色葡萄球菌的生存至关重要。通过计算机分析，该酶被评估为金黄色葡萄球菌的潜在药物靶点。使用枯草芽孢杆菌的 1TD9 链'A'作为模板，在 2.75 Å的分辨率下对来自金黄色葡萄球菌的磷酸转乙酰酶的 3D 结构进行建模。通过 PROCHECK、WHAT IF 和 SuperPose 对生成的模型进行了验证。通过 Molegro virtual docker 使用生成的锌数据库配体库进行对接。配体库是在 Lipinski 五规则的限制内生成的。根据对接得分，选择了五个分子进行 ADME/TOX 分析，并进行药效团模型生成。潜在抑制剂的锌 ID 为 ZINC08442078、ZINC8442200、ZINC 8442087 和 ZINC 8442184，被发现是磷酸转乙酰酶的药理学活性拮抗剂。这些分子通过 START 计划被评估为非致癌和持久的分子。
