Laboratory of Quantum and Computational Chemistry, Faculty of Chemistry and Pharmacy, Sofia University "St. Kliment Ohridski", 1 James Bourchier boulevard, Sofia 1164, Bulgaria.
J Phys Chem B. 2021 Jul 22;125(28):7598-7612. doi: 10.1021/acs.jpcb.1c00488. Epub 2021 Jul 12.
Active targeting is a prospective strategy for controlled drug delivery to malignant tumor tissues. One of the approaches relies on recognition of a bioactive ligand by a receptor expressed abundantly on the surface of cancer cell membranes. A promising ligand-receptor pair is folic acid (or its dianionic form, folate) combined with the folate receptor-α (FRα). A number of targeting drug delivery systems based on folate have been suggested, but the mechanism of binding of the ligand or its derivatives to the receptor is not fully known at the molecular level. The current study summarizes the results from unbiased all-atom molecular dynamics simulations at physiological conditions describing the binding of two forms of folate and four of its synthetically available derivatives to FRα. The models (ca. 185,000 atoms) contain one receptor molecule, embedded in the outer leaflet of a lipid bilayer, and one ligand, all immersed in saline. The bilayer represents a human cancer cell membrane and consists of 370 asymmetrically distributed lipid molecules from 35 types. The ability of the vector molecules to bind to the receptor, the position of binding, and the interactions between them are analyzed. Spontaneous binding on the nanosecond scale is observed for all molecules, but its time, position, and persistence depend strongly on the ligand. Only folate, 5-methyltetrahydrofolate, and raltitrexed bind selectively at the active site of the receptor. Two binding poses are observed, one of them (realized by raltitrexed) corresponding qualitatively to that reported for the crystallographic structure of the complex folate-FRα. Pemetrexed adsorbs nonspecifically on the protein surface, while methotrexate and pteroyl ornithine couple much less to the receptor. The molecular simulations reproduce qualitatively correctly the relative binding affinity measured experimentally for five of the ligands. Analysis of the interactions between the ligands and FRα shows that in order to accomplish specific binding to the active site, a combination of hydrogen bonding, π-stacking, and van der Waals and Coulomb attraction should be feasible simultaneously for the vector molecule. The reported results demonstrate that it is possible to observe receptor-ligand binding without applying bias by representing the local environment as close as possible and contain important molecular-level guidelines for the design of folate-based systems for targeted delivery of anticancer drugs.
主动靶向是一种将药物靶向递送至恶性肿瘤组织的有前景的策略。其中一种方法依赖于识别大量表达在癌细胞表面上的生物活性配体与受体的相互作用。叶酸（或其二价阴离子形式，即叶酸）与叶酸受体-α（FRα）的结合是一种很有前途的配体-受体对。已经提出了许多基于叶酸的靶向药物递送系统，但配体或其衍生物与受体结合的机制在分子水平上尚未完全了解。本研究总结了在生理条件下进行的无偏全原子分子动力学模拟的结果，这些模拟描述了两种叶酸形式和四种其合成可得的衍生物与 FRα 的结合。这些模型（约 185000 个原子）包含一个受体分子，嵌入在脂质双层的外叶中，以及一个配体，全部沉浸在盐水中。双层代表了人类癌细胞膜，由 35 种不对称分布的 370 个脂质分子组成。分析了载体分子与受体结合的能力、结合位置以及它们之间的相互作用。所有分子都在纳秒尺度上自发结合，但结合的时间、位置和持久性强烈依赖于配体。只有叶酸、5-甲基四氢叶酸和雷替曲塞选择性地结合在受体的活性部位。观察到两种结合构象，其中一种（由雷替曲塞实现）与复合物叶酸-FRα 的晶体结构报告的构象定性对应。培美曲塞非特异性地吸附在蛋白质表面，而甲氨蝶呤和蝶酰鸟氨酸与受体的结合较少。分子模拟定性地再现了实验测量的五种配体的相对结合亲和力。对配体与 FRα 之间的相互作用进行分析表明，为了实现对活性部位的特异性结合，载体分子应该同时具有氢键、π-堆积和范德华力和库仑吸引力的组合。报告的结果表明，有可能通过尽可能接近地表示局部环境来观察受体-配体结合，而无需施加偏见，并为基于叶酸的靶向递药系统的设计提供了重要的分子水平指导。
