FtsZ,一种细菌细胞分裂蛋白,对于组装在细菌胞质分裂中至关重要的收缩Z环至关重要。因此,抑制FtsZ可以阻碍原丝,破坏FtsZ和其他相关的蛋白质至关重要的细胞分裂机制。进行计算机药物相互作用研究,以确定抑制FtsZ蛋白的新型候选药物,旨在预防多重耐药(MDR)伤寒沙门氏菌。基于哌啶化合物进行数据挖掘,随后对其进行了安全的药代动力学筛选。符合有利的药物相似性标准的化合物进行针对FtsZ药物靶标的虚拟筛选。选择两个化合物进行分子对接和分子动力学模拟,以验证目标蛋白与潜在化合物之间的结合亲和力和稳定性。筛选了哌啶类似物的400种同工型,其中发现有效的化合物ZINC000000005416具有高结合亲和力(-8.49kcal/mol)和低解离常数(0.597µM)。通过氢键验证了ZINC000000005416显示的最高结合亲和力,疏水相互作用,和盐与细胞分裂调节蛋白的功能域桥接。对接纵断面,当与分子动力学模拟(MDS)相关时,描绘了FtsZ-ZINC000000005416复合物的稳定轨迹和相容构象变化。使用分子力学-泊松玻尔兹曼表面积(MM/PBSA)模块,通过自由能计算验证了稳定的模拟轨迹。低能量构象,尽管仿真轨迹证实了ZINC000000005416-FtsZ的稳定相互作用,这鼓励了实验验证。这项研究鼓励进一步探索化合物ZINC000000005416作为抑制FtsZ蛋白对抗MDR伤寒沙门氏菌的候选药物。由RamaswamyH.Sarma沟通。
FtsZ, a bacterial cell division protein, is essential for assembling the contractile Z-ring crucial in bacterial cytokinesis. Consequently, inhibiting FtsZ could impede proto-filaments, disrupting FtsZ and other associated proteins vital for cell division machinery. Conduct an in-silico drug interaction
study to identify novel drug candidates that inhibit the FtsZ protein, aiming to prevent Multi-Drug Resistant (MDR) Salmonella Typhi. Data mining was performed based on piperidine compounds, which were subsequently screened for safe pharmacokinetic profiles. Compounds that met favorable drug-likeness criteria underwent virtual screening against the FtsZ drug target. Two compounds were chosen for molecular docking and molecular dynamic simulation to verify the binding affinity and stability between the target protein and the potential compounds. The 400 isoforms of piperidine analogues were curated, among them potent compound ZINC000000005416 found to possess high binding affinity (-8.49 kcal/mol) and low dissociation constant (0.597 µM). The highest binding affinity shown by ZINC000000005416 was validated by hydrogen bonds, hydrophobic interaction, and salt bridges with the functional domain of the cell division regulatory protein. Docking profiles, when correlated with molecular dynamic simulation (MDS) depicted stable trajectories and compatible conformational changes in the FtsZ-ZINC000000005416 complex. The stable simulated trajectories were validated through free-energy calculations using the Molecular Mechanics-Poisson Boltzmann Surface Area (MM/PBSA) module. Low energy conformations, although the simulation trajectory confirmed the stable ZINC000000005416-FtsZ interaction, which encouraged experimental validations. This
study encourages further exploration of the compound ZINC000000005416 as a drug candidate inhibiting FtsZ protein against MDR Salmonella Typhi.Communicated by Ramaswamy H. Sarma.