Department of Microbiology, Shivaji University, Vidyanagar, Kolhapur, 416004, Maharashtra, India; Rayat Institute of Research and Development (RIRD), Satara, 415001, Maharashtra, India.
Structural Bioinformatics Unit, Department of Biochemistry, Shivaji University, Vidyanagar, Kolhapur, 416004, Maharashtra, India.
Comput Biol Med. 2023 Jun;159:106965. doi: 10.1016/j.compbiomed.2023.106965. Epub 2023 Apr 20.
Vancomycin resistance in enterococci mainly arises due to alteration in terminal peptidoglycan dipeptide. A comprehensive structural analysis for substrate specificity of dipeptide modifying d-Alanine: d-Serine ligase (Ddls) is essential to screen its inhibitors for combating vancomycin resistance. In this study modeled 3D structure of EgDdls from E. gallinarum was used for structure based virtual screening (SBVS) of oxadiazole derivatives. Initially, fifteen oxadiazole derivatives were identified as inhibitors at the active site of EgDdls from PubChem database. Further, four EgDdls inhibitors were evaluated using pharmacokinetic profile and molecular docking. The results of molecular docking showed that oxadiazole inhibitors could bind preferentially at ATP binding pocket with the lowest binding energy. Further, molecular dynamics simulation results showed stable behavior of EgDdls in complex with screened inhibitors. The residues Phe172, Lys174, Glu217, Phe292, and Asn302 of EgDdls were mainly involved in interactions with screened inhibitors. Furthermore, MM-PBSA calculation showed electrostatic and van der Waals interactions mainly contribute to overall binding energy. The PCA analysis showed motion of central domain and omega loop of EgDdls. This is involved in the formation of native dipeptide and stabilized after binding of 2-(1-(Ethylsulfonyl) piperidin-4-yl)-5-(furan-2-yl)-1,3,4-oxadiazole, which could be reason for the inhibition of EgDdls. Hence, in this study we have screened inhibitors of EgDdls which could be useful to alleviate the vancomycin resistance problem in enterococci, involved in hospital-acquired infections, especially urinary tract infections (UTI).
肠球菌的万古霉素耐药性主要是由于末端肽聚糖二肽的改变引起的。对二肽修饰 d-丙氨酸：d-丝氨酸连接酶（Ddls）的底物特异性进行全面的结构分析对于筛选其抑制剂以对抗万古霉素耐药性至关重要。在这项研究中，使用来自鸡肠球菌的 EgDdls 的 3D 结构模型进行了基于结构的虚拟筛选（SBVS），以筛选氧杂二唑衍生物。最初，从 PubChem 数据库中鉴定出 15 种氧杂二唑衍生物作为 EgDdls 的活性部位抑制剂。此外，使用药代动力学特征和分子对接评估了四种 EgDdls 抑制剂。分子对接结果表明，氧杂二唑抑制剂可以优先与 ATP 结合口袋结合，结合能最低。此外，分子动力学模拟结果表明，筛选出的抑制剂与 EgDdls 复合物的行为稳定。EgDdls 的残基 Phe172、Lys174、Glu217、Phe292 和 Asn302 主要参与与筛选出的抑制剂的相互作用。此外，MM-PBSA 计算表明静电和范德华相互作用主要贡献于整体结合能。PCA 分析显示 EgDdls 的中心结构域和 ω 环的运动。这涉及天然二肽的形成，并在结合 2-(1-(乙基磺酰基)哌啶-4-基)-5-(呋喃-2-基)-1,3,4-氧杂二唑后稳定，这可能是 EgDdls 抑制的原因。因此，在这项研究中，我们筛选了 EgDdls 的抑制剂，这可能有助于缓解肠球菌的万古霉素耐药问题，肠球菌参与医院获得性感染，特别是尿路感染（UTI）。
