Molecular Bio-computation and Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
College of Pharmacy and Pharmaceutical Sciences, Florida Agricultural and Mechanical University, FAMU, Tallahassee, FL, 32307, USA.
Protein J. 2019 Apr;38(2):142-150. doi: 10.1007/s10930-019-09820-z.
The constitutive BCR-ABL1 active protein fusion has been identified as the main cause of chronic myeloid leukemia. The emergence of T334I and D381N point mutations in BCR-ABL1 confer drug resistance. Recent experimental studies show a synergistic effect in suppressing this resistance when Nilotinib and Asciminib are co-administered to target both the catalytic and allosteric binding site of BCR-ABL1 oncoprotein, respectively. However, the structural mechanism by which this synergistic effect occurs has not been clearly elucidated. To obtain insight into the observed synergistic effect, molecular dynamics simulations have been employed to investigate the inhibitory mechanism as well as the structural dynamics that characterize this effect. Structural dynamic analyses indicate that the synergistic binding effect results in a more compact and stable protein conformation. In addition, binding free energy calculation suggests a dominant energy effect of nilotinib during co-administration. van der Waals energy interactions were observed to be the main energy component driving this synergistic effect. Furthermore, per-residue energy decomposition analysis identified Glu481, Ser453, Ala452, Tyr454, Phe401, Asp400, Met337, Phe336, Ile334, And Val275 as key residues that contribute largely to the synergistic effect. The findings highlighted in this study provide a molecular understanding of the dynamics and mechanisms that mediate the synergistic inhibition in BCR-ABL1 protein in chronic myeloid leukemia treatment.
组成型 BCR-ABL1 活性蛋白融合已被确定为慢性髓性白血病的主要原因。BCR-ABL1 中的 T334I 和 D381N 点突变的出现赋予了药物耐药性。最近的实验研究表明，当尼洛替尼和 ASCiminib 分别靶向 BCR-ABL1 癌蛋白的催化和变构结合位点时，联合使用会产生协同抑制作用。然而，这种协同作用发生的结构机制尚未明确阐明。为了深入了解观察到的协同作用，我们采用分子动力学模拟来研究抑制机制以及表征这种效应的结构动力学。结构动态分析表明，协同结合效应导致更紧凑和稳定的蛋白质构象。此外，结合自由能计算表明，在联合给药时，尼洛替尼具有主导的能量效应。观察到范德华相互作用是驱动这种协同效应的主要能量组成部分。此外，残基能量分解分析确定 Glu481、Ser453、Ala452、Tyr454、Phe401、Asp400、Met337、Phe336、Ile334 和 Val275 是对协同效应贡献较大的关键残基。本研究中的发现提供了对慢性髓性白血病治疗中 BCR-ABL1 蛋白协同抑制的动力学和机制的分子理解。
