Computational predictions of binding affinities to dihydrofolate reductase:: Synthesis and biological evaluation of methotrexate analogues
Computational predictions of binding affinities to dihydrofolate reductase:: Synthesis and biological evaluation of methotrexate analogues
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DOI：
10.1021/jm0009639
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发表时间：
2000-10-19
影响因子：
7.3
通讯作者：
Hallberg, A
中科院分区：
文献类型：
--
作者：
Graffner-Nordberg, M;Marelius, J;Hallberg, A
通过自由能扰动模拟估计了四种新的潜在抗叶酸剂（在两个芳香系统之间含有酯键）与人二氢叶酸还原酶的相对结合亲和力。合成了预计对人二氢叶酸还原酶表现出最高结合亲和力的酯类似物和参考酯（在结构上与甲氨蝶呤更相关）。根据测量的 IC50 值推论，尽管实验测量表明亲和力存在较大差异，但计算出的配体排序是正确的。在新型抗叶酸剂中，最有效的抑制剂表现出与甲氨蝶呤相似的药代动力学特征，但在大鼠体内复杂的抗关节炎模型中缺乏活性。
The relative binding affinities to human dihydrofolate reductase of four new potential antifolates, containing ester linkages between the two aromatic systems, were estimated by free energy perturbation simulations. The ester analogue, predicted to exhibit the highest binding affinity to human dihydrofolate reductase, and a reference ester (more structurally related to methotrexate) were synthesized. As deduced from the measured IC50 values, the calculated ranking of the ligands was correct although a greater difference in affinity was indicated by the experimental measurements. Among the new antifolates the most potent inhibitor exhibited a similar pharmacokinetic profile to methotrexate but lacked activity in a complex antiarthritic model in rat in vivo.