Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Bioorg Med Chem Lett. 2013 Jul 15;23(14):4166-71. doi: 10.1016/j.bmcl.2013.05.033. Epub 2013 May 18.
As increasing drug-resistance poses an emerging threat to public health, the development of novel antibacterial agents is critical. We developed a workflow consisting of various methods for de novo design. In the workflow, 2D-QSAR model based on molecular fingerprints was constructed to extract the bioactive molecular fingerprints from a data set of DNA-gyrase inhibitors with new structure and mechanism. These fingerprints were converted into molecular fragments which were recombined to generate compound library. The new compound library was virtually screened by LigandFit and Gold docking, and the results were further investigated by pharmacophore validation and binding mode analysis. The workflow successfully achieved a potential DNA-gyrase inhibitor. It could be applied to design more novel potential DNA-gyrase inhibitors and provide theoretical basis for further optimization of the hit compounds.
随着耐药性的不断增加对公共健康构成了新的威胁，开发新型抗菌药物至关重要。我们开发了一个包含各种从头设计方法的工作流程。在该工作流程中，基于分子指纹的 2D-QSAR 模型被构建用于从具有新结构和机制的 DNA 拓扑异构酶抑制剂数据集提取生物活性分子指纹。这些指纹被转化为分子片段，然后进行重组以生成化合物库。新的化合物库通过 LigandFit 和 Gold 对接进行虚拟筛选，并通过药效团验证和结合模式分析进一步研究结果。该工作流程成功地获得了一种潜在的 DNA 拓扑异构酶抑制剂。它可以应用于设计更多新型潜在的 DNA 拓扑异构酶抑制剂，并为进一步优化命中化合物提供理论依据。
