本研究阐明了氨甲喋呤的结构和抗癌性质，以及其抗病毒特性。通过半经验AM1方法研究了氨甲喋呤的偏好构象，并用密度泛函（DFT/B3LYP）方法和6-311++G(d,p)基组对得到的能量最低构型进行了优化。利用相同水平的理论计算了优化结构的振动频率，并与实验值进行了比较。基于计算的振动模态的潜在能分布（PED）进行了振动分配。对优化结构进行了分子静电势（MEP）和前线分子轨道（HOMO，LUMO）分析，并对其化学反应性进行了研究。为了揭示氨甲喋呤作为抗癌和抗COVID-19药物的生物活性，将氨甲喋呤与DNA、αIIBβ3和α5β1整合素、人类二氢叶酸还原酶、SARS-CoV-2的主要蛋白酶（Mpro）以及SARS-CoV-2/ACE2复合受体进行了对接。阐明了氨甲喋呤与受体的结合机制。分子对接结果显示，氨甲喋呤与DNA（-8.2 kcal/mol）、αIIBβ3和α5β1整合素（分别为-9.0和-10.8 kcal/mol）、人类二氢叶酸还原酶（-9.7 kcal/mol）、SARS-CoV-2的Mpro（-6.7 kcal/mol）以及SARS-CoV-2/ACE2复合受体（-8.1 kcal/mol）之间存在强烈的相互作用。此外，在分子对接计算后，将氨甲喋呤与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的全原子分子动力学模拟，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，氨甲喋呤可能显著抑制SARS-CoV-2的感染。因此，本研究展示了氨甲喋呤作为抗癌和抗COVID-19药物的生物活性的多样性。Ramaswamy H. Sarma传达。

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, αIIBβ3 and α5β1integrins, human dihydrofolate reductase, main protease (Mpro) 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), αIIBβ3 and α5β1 integrins (-9.0 and -10.8 kcal/mol, respectively), human dihydrofolate reductase (-9.7 kcal/mol), Mpro 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.