Physics Department, Science Faculty, Istanbul University, Istanbul, Turkey.
Opticianry Program, Vocational School, Istanbul Kultur University, Istanbul, Turkey.
J Biomol Struct Dyn. 2024 Sep;42(15):7773-7794. doi: 10.1080/07391102.2023.2245493. Epub 2023 Aug 11.
In this study, the structural and anticancer properties of aminopterin, as well as its antiviral characteristics, were elucidated. The preferred conformations of the title molecule were investigated with semiempirical AM1 method, and the obtained the lowest energy conformer was then optimized by using density functional (DFT/B3LYP) method with 6-311++G(d,p) as basis set. The vibrational frequencies of the optimized structure were calculated by the same level of theory and were compared with the experimental values. The vibrational assignments were performed based on the computed potential energy distribution (PED) of the vibrational modes. The molecular electrostatic potential (MEP) and frontier molecular orbitals (HOMO, LUMO) analyses were carried out for the optimized structure and the chemical reactivity has been scrutinized. To enlighten the biological activity of aminopterin as anticancer and anti-COVID-19 agents, aminopterin was docked into DNA, αβ and αβintegrins, human dihydrofolate reductase, main protease (M) of SARS-CoV-2 and SARS-CoV-2/ACE2 complex receptor. The binding mechanisms of aminopterin with the receptors were clarified. The molecular docking results revealed the strong interaction of the aminopterin with DNA (-8.2 kcal/mol), αβ and αβ integrins (-9.0 and -10.8 kcal/mol, respectively), human dihydrofolate reductase (-9.7 kcal/mol), M of SARS-CoV-2 (-6.7 kcal/mol), and SARS-CoV-2/ACE2 complex receptor (-8.1 kcal/mol). Moreover, after molecular docking calculations, top-scoring ligand-receptor complexes of the aminopterin with SARS-CoV-2 enzymes (6M03 and 6M0J) were subjected to 50 ns all-atom MD simulations to investigate the ligand-receptor interactions in more detail, and to determine the binding free energies accurately. The predicted results indicate that the aminopterin may significantly inhibit SARS-CoV-2 infection. Thus, in this study, as both anticancer and anti-COVID-19 agents, the versatility of the biological activity of aminopterin was shown.Communicated by Ramaswamy H. Sarma.
在这项研究中，阐明了氨基喋呤的结构和抗癌特性及其抗病毒特性。采用半经验 AM1 方法研究了标题分子的优先构象，然后使用密度泛函（DFT/B3LYP）方法和 6-311++G(d,p)作为基组对获得的最低能量构象进行了优化。用相同的理论水平计算了优化结构的振动频率，并与实验值进行了比较。根据计算得到的振动模式势能分布（PED）进行了振动分配。对优化结构进行了分子静电势（MEP）和前沿分子轨道（HOMO、LUMO）分析，并对其化学反应性进行了研究。为了阐明氨基喋呤作为抗癌和抗 COVID-19 药物的生物活性，将氨基喋呤对接进入 DNA、αβ和αβ整合素、人二氢叶酸还原酶、SARS-CoV-2 的主要蛋白酶（M）和 SARS-CoV-2/ACE2 复合物受体。阐明了氨基喋呤与受体的结合机制。分子对接结果表明，氨基喋呤与 DNA（-8.2 kcal/mol）、αβ和αβ整合素（分别为-9.0 和-10.8 kcal/mol）、人二氢叶酸还原酶（-9.7 kcal/mol）、SARS-CoV-2 的 M（-6.7 kcal/mol）和 SARS-CoV-2/ACE2 复合物受体（-8.1 kcal/mol）具有很强的相互作用。此外，在分子对接计算后，对氨基喋呤与 SARS-CoV-2 酶（6M03 和 6M0J）的得分最高的配体-受体复合物进行了 50 ns 全原子 MD 模拟，以更详细地研究配体-受体相互作用，并准确确定结合自由能。预测结果表明，氨基喋呤可能显著抑制 SARS-CoV-2 感染。因此，在这项研究中，作为抗癌和抗 COVID-19 药物，氨基喋呤的生物活性具有多功能性。由 Ramaswamy H. Sarma 交流。
