Identifying novel therapeutic inhibitors to target FMS-like tyrosine kinase-3 (FLT3) against acute myeloid leukemia: a molecular docking, molecular dynamics, and DFT study

Around 30% of acute myeloid leukemia (AML) patients have triggering mutations in Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (FLT3), which has been suggested as a possible therapeutic candidate for AML therapy. Many tyrosine kinase inhibitors are available and have a wide variety of applications in the treatment of cancer by inhibiting subsequent steps of cell proliferation. Therefore, our study aims to identify effective antileukemic agents against FLT3 gene. Initially, well-known antileukemic drug candidates have been chosen to generate a structure-based pharmacophore model to assist the virtual screening of 217,77,093 compounds from the Zinc database. The final hits compounds were retrieved and evaluated by docking against the target protein, where the top four compounds have been selected for the analysis of ADMET. Based on the density functional theory (DFT), the geometry optimization, frontier molecular orbital (FMO), HOMO-LUMO, and global reactivity descriptor values have been evaluated that confirming a satisfactory profile and reactivity order for the selected candidates. In comparison to control compounds, the docking results revealed that the four compounds had substantial binding energies (-11.1 to −11.5 kcal/mol) with FLT3. The physicochemical and ADMET (adsorption, distribution, metabolism, excretion, toxicity) prediction results corresponded to the bioactive and safe candidates. Molecular dynamics (MD) confirmed the better binding affinity and stability compared to gilteritinib as a potential FLT3 inhibitor. In this study, a computational approach has been performed that found a better docking and dynamics score against target proteins, indicating potent and safe antileukemic agents, furthermore <i>in-vivo</i> and <i>in-vitro</i> investigations are recommended. Communicated by Ramaswamy H. Sarma约30%的急性髓系白血病（acute myeloid leukemia, AML）患者携带猫McDonough肉瘤（Feline McDonough Sarcoma, FMS）样酪氨酸激酶3（FLT3）的激活性突变，该靶点被认为是AML治疗的潜在候选靶点。目前已有多种酪氨酸激酶抑制剂（tyrosine kinase inhibitor），其通过阻断细胞增殖的后续信号通路，在癌症治疗中有着广泛应用。因此本研究旨在筛选针对FLT3基因的有效抗白血病药物。本研究初始阶段选取经典抗白血病候选药物构建基于结构的药效团模型，用于辅助从Zinc数据库中虚拟筛选21777093个化合物。最终获得的命中化合物经靶点蛋白分子对接验证并评估后，选取排名前四的化合物进行ADMET（吸收、分布、代谢、排泄、毒性）分析。基于密度泛函理论（density functional theory, DFT），本研究对所选候选化合物开展了几何优化、前线分子轨道（frontier molecular orbital, FMO）、HOMO-LUMO以及全局反应性描述符值的计算，结果证实所选候选化合物具备良好的性质与反应性顺序。与对照化合物相比，分子对接结果显示这4种化合物与FLT3具有显著的结合能（-11.1至-11.5 kcal/mol）。理化性质与ADMET预测结果表明，这些候选化合物属于兼具生物活性与安全性的候选药物。分子动力学（molecular dynamics, MD）模拟结果证实，相较于吉列替尼（gilteritinib），这些作为潜在FLT3抑制剂的化合物具有更优的结合亲和力与结构稳定性。本研究通过计算生物学策略，筛选得到了针对靶点蛋白具有优异对接与动力学评分的强效安全抗白血病候选药物，后续建议开展体内（in-vivo）与体外（in-vitro）实验验证。本文由Ramaswamy H. Sarma通讯刊发。