Nivón-Ramirez Didier, Galván-García Emir A, Ponce-Pérez León D, Gómez-Balderas Rodolfo
Laboratorio de Fisicoquímica Analítica, Unidad de Investigación Multidisciplinaria, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Cuautitlán Izcalli, Estado de México, 54714, Mexico.
Laboratorio de Fisicoquímica Analítica, Unidad de Investigación Multidisciplinaria, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Cuautitlán Izcalli, Estado de México, 54714, Mexico.
Comput Biol Med. 2025 Mar;186:109728. doi: 10.1016/j.compbiomed.2025.109728. Epub 2025 Jan 24.
Bacterial resistance is a global public health problem because of the ineffectiveness of conventional antibiotics against super pathogens. To counter this situation, the search for or design of new molecules is essential to inhibit the key proteins involved in several stages of bacterial infection. One of these key proteins is DNA gyrase, which is responsible for packaging and unfolding of DNA chains during replication. Virtual screening calculations of 583,900 molecules against the ATPase site of DNA gyrase (PDB ID 7PQM) resulted in three promising molecules (Z927783420, Z4422201766, and Z2440107042) with significant binding modes at the active site, according to molecular docking studies. Additionally, they exhibited lower toxicological profiles than the previously reported 80S inhibitors. Molecular dynamics calculations revealed crucial interactions responsible for the inhibition process, with residues ASP87, GLU94, and ASN60 belonging to the ATPase site. On the other hand, the binding energy calculated using the MM/GBSA protocol highlighted Z2440107042 as the most promising inhibitor, with the best binding energy (-74.77 kcal/mol), suggesting that this molecule is a strong candidate for further biological studies.
由于传统抗生素对超级病原体无效，细菌耐药性已成为一个全球性的公共卫生问题。为应对这种情况，寻找或设计新分子对于抑制细菌感染多个阶段中涉及的关键蛋白质至关重要。这些关键蛋白质之一是DNA旋转酶，它负责在复制过程中对DNA链进行包装和展开。根据分子对接研究，针对DNA旋转酶的ATP酶位点（PDB ID 7PQM）对583,900个分子进行虚拟筛选计算，得到了三个有前景的分子（Z927783420、Z4422201766和Z2440107042），它们在活性位点具有显著的结合模式。此外，它们的毒理学特征比先前报道的80S抑制剂更低。分子动力学计算揭示了负责抑制过程的关键相互作用，其中ASP87、GLU94和ASN60残基属于ATP酶位点。另一方面，使用MM/GBSA协议计算的结合能突出显示Z2440107042是最有前景的抑制剂，具有最佳结合能（-74.77千卡/摩尔），这表明该分子是进一步生物学研究的有力候选者。
