Computational Chemistry Laboratory, Institute of Chemistry, University of Brasilia, Brasilia, DF, 70910-900, Brazil.
J Mol Model. 2021 Oct 1;27(10):309. doi: 10.1007/s00894-021-04925-8.
Chronic myeloid leukemia (CML) is a pathological condition associated with the uncontrolled proliferation of white blood cells and respective loss of function. Imatinib was the first drug that could effectively treat this condition, but its use is hindered by the development of mutations of the BCR-ABL protein, which are the cause of resistance. Therefore, dasatinib and afatinib present similarities that can be explored to discover new molecules capable of overcoming the effects of imatinib. Afatinib exhibited electronic and docking behavior, indicating that a replacement with some minor modifications could design a new potential inhibitor. The amide group in each candidate is clearly of pharmacophoric importance, and it needs to concentrate a negative region. Sulfur group presents a good pharmacophoric profile, which was shown by dasatinib results, adding to the influence of the Met318 residue in the target protein active site configuration. This behavior suggests that the sulfur atom and other fragments that have an affinity for the methionine sidechain may provide a significant positive effect when present in TKI molecules such as afatinib or dasatinib.
慢性髓性白血病（CML）是一种与白细胞不受控制的增殖和相应功能丧失相关的病理状况。伊马替尼是第一种能够有效治疗这种疾病的药物，但由于 BCR-ABL 蛋白的突变，其使用受到了阻碍，这些突变是耐药性的原因。因此，达沙替尼和阿法替尼具有相似之处，可以探索发现新的分子，以克服伊马替尼的作用。阿法替尼表现出电子和对接行为，表明可以通过一些微小的修饰来设计新的潜在抑制剂。每个候选物中的酰胺基团显然具有药效基团的重要性，需要集中在一个负区域。硫基团表现出良好的药效基团特征，这一点从达沙替尼的结果中可以看出，这增加了靶蛋白活性位点构象中 Met318 残基的影响。这种行为表明，当存在于阿法替尼或达沙替尼等 TKI 分子中时，硫原子和其他与甲硫氨酸侧链有亲和力的片段可能会产生显著的积极影响。
