Silva Pedro J
FP-I3ID, FP-BHS, Faculdade de Ciências da Saúde, Universidade Fernando Pessoa, 4200-150 Porto, Portugal.
UCIBIO@REQUIMTE, BioSIM, Departamento de Biomedicina, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal.
Antibiotics (Basel). 2022 Jun 7;11(6):779. doi: 10.3390/antibiotics11060779.
Resistance to trimethoprim and other antibiotics targeting dihydrofolate reductase may arise in bacteria harboring an atypical, plasmid-encoded, homotetrameric dihydrofolate reductase, called R67 DHFR. Although developing inhibitors to this enzyme may be expected to be promising drugs to fight trimethoprim-resistant strains, there is a paucity of reports describing the development of such molecules. In this manuscript, we describe the design of promising lead compounds to target R67 DHFR. Density-functional calculations were first used to identify the modifications of the pterin core that yielded derivatives likely to bind the enzyme and not susceptible to being acted upon by it. These unreactive molecules were then docked to the active site, and the stability of the docking poses of the best candidates was analyzed through triplicate molecular dynamics simulations, and compared to the binding stability of the enzyme-substrate complex. Molecule ([6-(methoxymethyl)-4-oxo-3,7-dihydro-4-pyrano[2,3-d]pyrimidin-2-yl]methyl-guanidinium) was shown by this methodology to afford extremely stable binding towards R67 DHFR and to prevent simultaneous binding to the substrate. Additional docking and molecular dynamics simulations further showed that this candidate also binds strongly to the canonical prokaryotic dihydrofolate reductase and to human DHFR, and is therefore likely to be useful to the development of chemotherapeutic agents and of dual-acting antibiotics that target the two types of bacterial dihydrofolate reductase.
携带一种非典型的、质粒编码的同四聚体二氢叶酸还原酶（称为R67 DHFR）的细菌可能会对甲氧苄啶和其他靶向二氢叶酸还原酶的抗生素产生耐药性。尽管开发针对这种酶的抑制剂有望成为对抗甲氧苄啶耐药菌株的药物，但描述此类分子开发的报道却很少。在本论文中，我们描述了靶向R67 DHFR的有前景的先导化合物的设计。首先使用密度泛函计算来确定蝶呤核心的修饰，这些修饰产生的衍生物可能与该酶结合且不易被其作用。然后将这些无反应性的分子对接至活性位点，并通过三次重复的分子动力学模拟分析最佳候选物对接构象的稳定性，并与酶 - 底物复合物的结合稳定性进行比较。通过这种方法表明，分子（[6 - （甲氧基甲基） - 4 - 氧代 - 3,7 - 二氢 - 4 - 吡喃并[2,3 - d]嘧啶 - 2 - 基]甲基 - 胍鎓）对R67 DHFR具有极其稳定的结合，并能阻止其与底物同时结合。进一步的对接和分子动力学模拟表明，该候选物还与典型的原核二氢叶酸还原酶和人二氢叶酸还原酶强烈结合，因此可能有助于开发针对两种类型细菌二氢叶酸还原酶的化疗药物和双效抗生素。
