Luo Minghao, Wang Hui, Zou Yi, Zhang Shengping, Xiao Jianhu, Jiang Guangde, Zhang Yihua, Lai Yisheng
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China.
School of Chemical Sciences, The University of Auckland, 23 Symonds St., Auckland 1142, New Zealand.
J Mol Graph Model. 2016 Jul;68:128-139. doi: 10.1016/j.jmgm.2016.06.011. Epub 2016 Jun 18.
Dot1-like protein (DOT1L) is a histone methyltransferase that has become a novel and promising target for acute leukemias bearing mixed lineage leukemia (MLL) gene rearrangements. In this study, a hierarchical docking-based virtual screening combined with molecular dynamic (MD) simulation was performed to identify DOT1L inhibitors with novel scaffolds. Consequently, 8 top-ranked hits were eventually identified and were further subjected to MD simulation. It was indicated that all hits could reach equilibrium with DOT1L in the MD simulation and further binding free energy calculations suggested that phenoxyacetamide-derived hits such as L01, L03, L04 and L05 exhibited remarkably higher binding affinity compared to other hits. Among them, L03 showed both the lowest glide score (-12.281) and the most favorable binding free energy (-303.9+/-16.5kJ/mol), thereby making it a promising lead for further optimization.
Dot1样蛋白（DOT1L）是一种组蛋白甲基转移酶，已成为携带混合谱系白血病（MLL）基因重排的急性白血病的新型且有前景的靶点。在本研究中，进行了基于分层对接的虚拟筛选并结合分子动力学（MD）模拟，以鉴定具有新型骨架的DOT1L抑制剂。最终鉴定出8个排名靠前的命中化合物，并对其进行了进一步的MD模拟。结果表明，在MD模拟中所有命中化合物都能与DOT1L达到平衡，进一步的结合自由能计算表明，苯氧基乙酰胺衍生的命中化合物如L01、L03、L04和L05与其他命中化合物相比表现出显著更高的结合亲和力。其中，L03的滑行评分最低（-12.281）且结合自由能最有利（-303.9±16.5kJ/mol），因此使其成为进一步优化的有前景的先导化合物。
