Introduction

Treatment failures of standard regimens and new strains egression are due to the augmented drug resistance conundrum. These confounding factors now became the drug designers spotlight to implement therapeutics against Helicobacter pylori strains and to safeguard infected victims with devoid of adverse drug reactions. Thereby, to navigate the chemical space for medicine, paramount vital drug target opting considerations should be imperative. The study is therefore aimed to develop potent therapeutic variants against an insightful extrapolative, common target LpxC as a follow-up to previous studies.

Methods

We explored the relationships between existing inhibitors and novel leads at the scaffold level in an appropriate conformational plasticity for lead-optimization campaign. Hierarchical-clustering and shape-based screening against an in-house library of > 21 million compounds resulted in panel of 11,000 compounds. Rigid-receptor docking through virtual screening cascade, quantum-polarized-ligand, induced-fit dockings, post-docking processes and system stability assessments were performed.

Results

After docking experiments, an enrichment performance unveiled seven ranked actives better binding efficiencies with Zinc-binding potency than substrate and in-actives (decoy-set) with ROC (1.0) and area under accumulation curve (0.90) metrics. Physics-based membrane permeability accompanied ADME/T predictions and long-range dynamic simulations of 250 ns chemical time have depicted good passive diffusion with no toxicity of leads and sustained consistency of lead1-LpxC in the physiological milieu respectively.

Conclusions

In the study, as these static outcomes obtained from this approach competed with the substrate and existing ligands in binding affinity estimations as well as positively correlated from different aspects of predictions, which could facilitate promiscuous new chemical entities against H. pylori.

中文翻译：

---

针对幽门螺杆菌的脂质-A 生物合成的有效抑制剂的分层聚类、支架挖掘练习和动力学模拟。

介绍

标准方案的治疗失败和新菌株的排出是由于耐药性难题的增加。这些混杂因素现在成为药物设计者关注的焦点，以实施针对幽门螺杆菌菌株的治疗并保护受感染的受害者没有药物不良反应。因此，为了在药物的化学空间中导航，最重要的药物靶点选择考虑应该是当务之急。因此，该研究旨在开发针对具有洞察力的外推共同目标 LpxC 的有效治疗变体，作为先前研究的后续行动。

方法

我们在适当的构象可塑性中探索了现有抑制剂与支架水平新先导之间的关系，以进行先导优化活动。针对超过 2100 万个化合物的内部库进行分层聚类和基于形状的筛选，产生了 11000 个化合物的面板。进行了通过虚拟筛选级联、量子极化配体、诱导拟合对接、对接后过程和系统稳定性评估的刚性受体对接。

结果

对接实验后，富集性能揭示了七种活性物质与锌结合效力的结合效率优于底物和非活性物质（诱饵集）与 ROC（1.0）和累积曲线下面积（0.90）指标。基于物理的膜渗透性伴随 ADME/T 预测和 250 ns 化学时间的长程动态模拟分别描绘了良好的被动扩散，无铅毒性和铅 1-LpxC 在生理环境中的持续一致性。

结论

在这项研究中，由于从这种方法获得的这些静态结果在结合亲和力估计中与底物和现有配体竞争，并且与预测的不同方面呈正相关，这可能促进混杂的新化学实体对抗幽门螺杆菌。