Through the open door: Preferential binding of dasatinib to the active form of BCR-ABL unveiled by in silico experiments
Through the open door: Preferential binding of dasatinib to the active form of BCR-ABL unveiled by in silico experiments
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DOI：
10.1016/j.molonc.2013.06.001
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发表时间：
2013-10-01
影响因子：
6.6
通讯作者：
Pricl, Sabrina
中科院分区：
文献类型：
--
作者：
Laurini, Erik;Posocco, Paola;Pricl, Sabrina
达沙替尼是第二代BCR-ABL抑制剂，获准用于治疗慢性粒细胞白血病患者，无论是在一线还是在伊马替尼耐药/不耐受的情况下。目前认为达沙替尼对蛋白质的高亲和力是由于其结合BCR-ABL激酶的活性和非活性构象的能力。在目前的工作中，使用最先进的分子模拟技术，我们证明了达沙替尼表现出高度选择性的优先选择活性（开放）BCR-ABL构象。通过使用三种不同的BCR-ABL构象（活性、非活性和中间非活性），我们表明，从热力学角度来看，达沙替尼对BCR-ABL的亲和力按以下顺序急剧降低：活性>替代非活性>非活性，这是由于内衬激酶结合口袋的单个残基的差异贡献以及伴随的激酶疏水性脊柱的稳定/不稳定。分子牵引实验也证实了这一趋势，因为相对于活性络合物对应物，从其非活性BCR-ABL络合物中提取达沙替尼所需的力显著降低，时间缩短。重要的是，我们的结果支持最近的NMR溶液结果，证明没有证据表明达沙替尼与BCR-ABL的非活性形式结合。（C）2013年欧洲生物化学学会联合会。Elsevier B. V.出版，保留所有权利。
Dasatinib is a second-generation BCR-ABL inhibitor approved for the treatment of patients with chronic myeloid leukemia, both in the frontline and in the imatinib-resistant/ intolerant settings. The high affinity of dasatinib for the protein is currently assumed to result from its ability to bind both the active and inactive conformations of the BCR-ABL kinase. In the present work, using state of the art molecular simulation techniques we prove that dasatinib exhibits a highly selective preference for the active (open) BCR-ABL conformation. By using three different BCR-ABL conformations (active, inactive, and intermediate inactive) we show that, from a thermodynamic standpoint, the affinity of dasatinib for BCR-ABL drastically decreases in the order: active > alternative inactive > inactive, as a result of differential contributions from the single residues lining the kinase binding pocket and the concomitant stabilization/destabilization of the kinase hydrophobic spine. Molecule-pulling experiments also corroborate this trend as significantly lower forces and smaller times are required to extract dasatinib from its inactive BCR-ABL complexes with respect to the active complex counterparts. Importantly, our results support recent NMR solution results demonstrating no evidence of dasatinib bound to the inactive form of BCR-ABL. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.