Department of Biochemistry and Biophysics, University of Kalyani, Nadia, Kalyani, 741235, West Bengal, India.
Department of Biotechnology, Sidho-Kanho-Birsha University, Ranchi-Purulia Road Campus, Near Sainik School, Purulia, 723104, West Bengal, India.
J Mol Model. 2022 Sep 5;28(10):295. doi: 10.1007/s00894-022-05301-w.
Pseudomonas aeruginosa is an opportunistic human pathogen. It synthesizes the poison called Hydrogen Cyanide (HCN). The synthesis of HCN is mediated by the enzyme HCN synthase which is obtained from the hcnABC operon and the transcription of the hcnABC operon is mediated by three proteins LasR, RhlR, and ANR. In our previous works, we analyzed the activation process of RhlR and LasR proteins by their cognate auto-inducer ligands (N-butanoyl-L-homoserine lactone and N-(3-oxododecanoyl)-homoserine lactone respectively). In this work, we attempted to identify some multi-targeting ligands which would be able to destroy the structural integrity of both the RhlR and LasR proteins using steered MD simulations. We used the virtual screening of ligand libraries, and for that purpose, we used the NCI drug database. We selected the top 4 ligands from our virtual screening experiments. We then tried to check their relative binding affinities with the LasR and RhlR proteins in comparison to their native auto-inducer ligands. Through this work, we were able to identify 4 such ligands which were capable of binding to both the RhlR and LasR proteins in a better way than their native auto-inducer ligands. The efficacies of these ligands to actually perturb the structural integrity of RhlR and LasR proteins could be tested in wet lab. The work is the first work in the field of structure-based drug design to come up with possible multi-targeting drug-like structures against the RhlR and LasR proteins from Pseudomonas aeruginosa.
铜绿假单胞菌是一种机会性病原体。它合成一种叫做氰化氢（HCN）的毒素。HCN 的合成是由 HCN 合酶介导的，该酶来自 hcnABC 操纵子，hcnABC 操纵子的转录由 LasR、RhlR 和 ANR 三种蛋白介导。在我们之前的工作中，我们分析了 LasR 和 RhlR 蛋白通过其同源自动诱导配体（分别为 N-丁酰基-L-高丝氨酸内酯和 N-（3-氧代十二烷酰基）-高丝氨酸内酯）的激活过程。在这项工作中，我们试图使用定向 MD 模拟来鉴定一些能够破坏 RhlR 和 LasR 蛋白结构完整性的多靶点配体。我们使用配体文库的虚拟筛选，为此，我们使用了 NCI 药物数据库。我们从虚拟筛选实验中选择了前 4 种配体。然后，我们试图检查它们与 LasR 和 RhlR 蛋白的相对结合亲和力，与它们的天然自动诱导配体进行比较。通过这项工作，我们能够识别出 4 种这样的配体，它们能够比天然自动诱导配体更好地结合 RhlR 和 LasR 蛋白。这些配体实际破坏 RhlR 和 LasR 蛋白结构完整性的效果可以在湿实验室中进行测试。这项工作是基于结构的药物设计领域的第一项工作，提出了针对铜绿假单胞菌的 RhlR 和 LasR 蛋白的可能的多靶点类似药物结构。
