A series of novel antifolates (32 compounds) were used to study the interactions with folate receptors α and β. The compounds had different sizes of methyl (-CH₃), carboxyl (-COOH), hydroxyl (-OH), and amino groups (-NH₂). The binding properties of the complexes were studied by molecular docking, molecular dynamic (MD) simulations, and MM/PBSA free energy calculations. The docked binding energies and modes were analyzed to identify compounds with good recognition of FRα from FRβ. The stable conformers, root mean square displacement, root mean square fluctuation free binding energy, and contribution of residues to the binding energy of the complexes were further analyzed to illustrate the interactions between the novel compounds and folate receptors. The data show that introducing long functional groups in folate will increase the binding affinity with FRα but will decrease the binding affinity with FRβ. The results provide a strategy for the design of novel antifolates targeted to FRα.

一系列新型抗叶酸剂（32 种化合物）用于研究与叶酸受体 α 和 β 的相互作用。这些化合物具有不同大小的甲基 (-CH ₃ )、羧基 (-COOH)、羟基 (-OH) 和氨基 (-NH ₂). 通过分子对接、分子动力学 (MD) 模拟和 MM/PBSA 自由能计算研究了复合物的结合特性。对对接的结合能和模式进行了分析，以确定对 FRα 和 FRβ 具有良好识别能力的化合物。进一步分析了稳定的构象异构体、均方根位移、均方根波动自由结合能以及残基对复合物结合能的贡献，以说明新型化合物与叶酸受体之间的相互作用。数据表明，在叶酸中引入长官能团会增加与 FRα 的结合亲和力，但会降低与 FRβ 的结合亲和力。该结果为设计针对 FRα 的新型抗叶酸剂提供了策略。