Department of Biomedical Sciences, College of Medicine, Chosun University, Gwangju 501-759, Korea.
Department of Cellular and Molecular Medicine, College of Medicine, Chosun University, Gwangju 501-759, Korea.
Int J Mol Sci. 2021 Nov 19;22(22):12511. doi: 10.3390/ijms222212511.
Overexpression and frequent mutations in FMS-like tyrosine kinase-3 (FLT3) are considered risk factors for severe acute myeloid leukemia (AML). Hyperactive FLT3 induces premature activation of multiple intracellular signaling pathways, resulting in cell proliferation and anti-apoptosis. We conducted the computational modeling studies of 40 pyrimidine-4,6-diamine-based compounds by integrating docking, molecular dynamics, and three-dimensional structure-activity relationship (3D-QSAR). Molecular docking showed that K644, C694, F691, E692, N701, D829, and F830 are critical residues for the binding of ligands at the hydrophobic active site. Molecular dynamics (MD), together with Molecular Mechanics Poison-Boltzmann/Generalized Born Surface Area, i.e., MM-PB(GB)SA, and linear interaction energy (LIE) estimation, provided critical information on the stability and binding affinity of the selected docked compounds. The MD study suggested that the mutation in the gatekeeper residue F691 exhibited a lower binding affinity to the ligand. Although, the mutation in D835 in the activation loop did not exhibit any significant change in the binding energy to the most active compound. We developed the ligand-based comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models. CoMFA ( = 0.802, = 0.983, and QF32 = 0.698) and CoMSIA ( = 0.725, = 0.965 and QF32 = 0.668) established the structure-activity relationship (SAR) and showed a reasonable external predictive power. The contour maps from the CoMFA and CoMSIA models could explain valuable information about the favorable and unfavorable positions for chemical group substitution, which can increase or decrease the inhibitory activity of the compounds. In addition, we designed 30 novel compounds, and their predicted pIC values were assessed with the CoMSIA model, followed by the assessment of their physicochemical properties, bioavailability, and free energy calculation. The overall outcome could provide valuable information for designing and synthesizing more potent FLT3 inhibitors.
FMS 样酪氨酸激酶 3（FLT3）的过表达和频繁突变被认为是严重急性髓性白血病（AML）的危险因素。过度活跃的 FLT3 诱导多个细胞内信号通路的过早激活，导致细胞增殖和抗凋亡。我们通过整合对接、分子动力学和三维结构-活性关系（3D-QSAR）对 40 种嘧啶-4,6-二胺类化合物进行了计算建模研究。分子对接表明，K644、C694、F691、E692、N701、D829 和 F830 是配体在疏水活性部位结合的关键残基。分子动力学（MD）与分子力学势能-波尔兹曼/广义 Born 表面面积（MM-PB(GB)SA）和线性相互作用能（LIE）估算一起，提供了有关所选对接化合物稳定性和结合亲和力的关键信息。MD 研究表明，位于门控残基 F691 上的突变对配体的结合亲和力较低。尽管在激活环中的 D835 突变对与最活跃化合物的结合能没有任何显著变化。我们开发了基于配体的比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）模型。CoMFA（ = 0.802， = 0.983，和 QF32 = 0.698）和 CoMSIA（ = 0.725， = 0.965 和 QF32 = 0.668）建立了结构-活性关系（SAR），并显示出合理的外部预测能力。CoMFA 和 CoMSIA 模型的轮廓图可以解释有关化学基团取代的有利和不利位置的有价值信息，这可以增加或减少化合物的抑制活性。此外，我们设计了 30 种新型化合物，并使用 CoMSIA 模型评估了它们的预测 pIC 值，随后评估了它们的物理化学性质、生物利用度和自由能计算。总体结果可为设计和合成更有效的 FLT3 抑制剂提供有价值的信息。
