The rising cases of resistance to existing antibiotics by Salmonella typhi, has made the development of novel drug candidates a necessity. In this study, a data set of antibacterial pyridine substituted coumarins were subjected to Virtual Screening against SipA effector protein of the bacterium. The compounds were geometry-optimized using Semi-empirical (pm3) method in Spartan 14 software, docked against the active sites of SipA using AutoDock Vina software. The molecule with the best docked score was selected as template and subjected to structural modifications leading to the design of a novel coumarin based drug candidate codenamed Y-1. The docking of Y-1 against SipA revealed that it binds to the target with ΔG value of − 9.1 kcal/mol. This value is better than − 6.8 kcal/mol obtained for ciprofloxacin used herein for quality assurance. Additionally, quantum mechanical calculations on Y-1 using DFT (B3LYP/6-31G* basis set) shows a wide energy gap of 3.44 eV and ω value of 1.47 eV, indicating its sound kinetic and thermodynamic stabilities. Y-1 was also found to possess good oral bioavailability and positive pharmacokinetic profiles. This is the first time coumarin derivatives are screened against an effector protein of Salmonella typhi. It is envisaged that the findings of this research will provide an excellent blueprint toward the development of novel antibiotics against Salmonella typhi.

中文翻译：

---

计算机辅助设计新型抗生素候选药物，以吡啶取代香豆素对抗伤寒沙门氏菌多重耐药菌株

伤寒沙门氏菌对现有抗生素产生耐药性的病例不断增加，使得开发新型候选药物成为必要。在这项研究中，对抗菌吡啶取代香豆素的数据集进行了针对细菌 SipA 效应蛋白的虚拟筛选。使用 Spartan 14 软件中的半经验 (pm3) 方法对化合物进行几何优化，并使用 AutoDock Vina 软件与 SipA 的活性位点对接。选择具有最佳对接分数的分子作为模板并进行结构修饰，从而设计出代号为 Y-1 的新型香豆素候选药物。 Y-1 与 SipA 的对接表明，它与靶标结合的 ΔG 值为 − 9.1 kcal/mol。该值优于本文使用的环丙沙星的-6.8 kcal/mol，以保证质量。此外，使用DFT（B3LYP/6-31G*基组）对Y-1进行的量子力学计算显示出3.44 eV的宽能隙和1.47 eV的ω值，表明其良好的动力学和热力学稳定性。 Y-1 还被发现具有良好的口服生物利用度和积极的药代动力学特征。这是首次针对伤寒沙门氏菌效应蛋白筛选香豆素衍生物。预计这项研究的结果将为开发针对伤寒沙门氏菌的新型抗生素提供良好的蓝图。