Department of Microbiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
Biology Department, Faculty of Sciences, Shehrekord University, Shahrekord, Iran.
Sci Rep. 2021 Jan 27;11(1):2390. doi: 10.1038/s41598-021-82009-6.
New Delhi metallo-β-lactamase variants and different types of metallo-β-lactamases have attracted enormous consideration for hydrolyzing almost all β-lactam antibiotics, which leads to multi drug resistance bacteria. Metallo-β-lactamases genes have disseminated in hospitals and all parts of the world and became a public health concern. There is no inhibitor for New Delhi metallo-β-lactamase-1 and other metallo-β-lactamases classes, so metallo-β-lactamases inhibitor drugs became an urgent need. In this study, multi-steps virtual screening was done over the NPASS database with 35,032 natural compounds. At first Captopril was extracted from 4EXS PDB code and use as a template for the first structural screening and 500 compounds obtained as hit compounds by molecular docking. Then the best ligand, i.e. NPC120633 was used as templet and 800 similar compounds were obtained. As a final point, ten compounds i.e. NPC171932, NPC100251, NPC18185, NPC98583, NPC112380, NPC471403, NPC471404, NPC472454, NPC473010 and NPC300657 had proper docking scores, and a 50 ns molecular dynamics simulation was performed for calculation binding free energy of each compound with New Delhi metallo-β-lactamase. Protein sequence alignment, 3D conformational alignment, pharmacophore modeling on all New Delhi metallo-β-lactamase variants and all types of metallo-β-lactamases were done. Quantum chemical perspective based on the fragment molecular orbital (FMO) method was performed to discover conserved and crucial residues in the catalytic activity of metallo-β-lactamases. These residues had similar 3D coordinates of spatial location in the 3D conformational alignment. So it is posibble that all types of metallo-β-lactamases can inhibit by these ten compounds. Therefore, these compounds were proper to mostly inhibit all metallo-β-lactamases in experimental studies.
新德里金属β-内酰胺酶变体和不同类型的金属β-内酰胺酶因其几乎能水解所有β-内酰胺类抗生素而引起了广泛关注，导致了多重耐药菌的产生。金属β-内酰胺酶基因已在医院和世界各地传播，并成为公共卫生关注的问题。目前还没有针对新德里金属β-内酰胺酶-1 和其他金属β-内酰胺酶类别的抑制剂，因此金属β-内酰胺酶抑制剂类药物成为当务之急。在这项研究中，我们对 NPASS 数据库中的 35032 种天然化合物进行了多步骤虚拟筛选。首先，从 4EXS PDB 代码中提取卡托普利，并将其用作第一个结构筛选的模板，通过分子对接获得 500 个命中化合物。然后，选择最佳配体 NPC120633 作为模板，获得 800 个类似化合物。最后，选择了 10 种化合物，即 NPC171932、NPC100251、NPC18185、NPC98583、NPC112380、NPC471403、NPC471404、NPC472454、NPC473010 和 NPC300657，它们的对接评分都比较合适，对每个化合物与新德里金属β-内酰胺酶的结合自由能进行了 50ns 的分子动力学模拟。对所有新德里金属β-内酰胺酶变体和所有类型的金属β-内酰胺酶进行了蛋白序列比对、3D 构象比对、药效团建模。基于碎片分子轨道（FMO）方法的量子化学分析，发现了金属β-内酰胺酶催化活性中的保守和关键残基。这些残基在 3D 构象比对中的空间位置具有相似的 3D 坐标。因此，这 10 种化合物有可能抑制所有类型的金属β-内酰胺酶。因此，这些化合物在实验研究中很有可能成为大多数金属β-内酰胺酶的抑制剂。
