Abulaiti Dilinazi, Tuerxun Niluopaer, Wang Huan, Ma Lina, Zhao Fang, Liu Yang, Hao Jianping
Hematologic Disease Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi 830011, China.
Hematologic Disease Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi 830011, China.
J Genet Eng Biotechnol. 2024 Dec;22(4):100444. doi: 10.1016/j.jgeb.2024.100444. Epub 2024 Nov 20.
Chronic Myeloid Leukemia (CML) is particularly challenging to treat due to the T315I BCR::ABL1 mutation. Although fungal metabolites are known for their pharmaceutical potential, none are approved for CML. Our study screened approximately 2000 fungal secondary metabolites to discover inhibitors targeting the T315I- BCR::ABL1 mutant protein.
We conducted comprehensive analyses to elucidate the interactions between the T315I-BCR::ABL1 mutant protein and selected fungal metabolites. These analyses included molecular docking, ADMET assessment, molecular dynamics simulations, principal components analysis, exploration of free energy landscapes, and per-residue decomposition.
We identified a range of binding affinities for fungal secondary metabolites, from -11.2 kcal/mol to -2.90 kcal/mol, with the co-crystal ponatinib showing a binding affinity of -9.9 kcal/mol. Notably, twenty seven fungal metabolites had affinities ≤ -10.0 kcal/mol, surpassing ponatinib. Eight compounds, including Phellifuropyranone A and Meshimakobnol B, showed favorable drug-likeness. Molecular dynamics parameters, including RMSD, RMSF, Rg, and SASA, confirmed that Phellifuropyranone A and Meshimakobnol B bind stably to the T315I-BCR::ABL1 mutant protein. Additionally, PCA, DCCM, and free energy landscapes analyses validated the consistency of the molecular dynamics parameters. MM/PBSA analysis indicated that Phellifuropyranone A (-22.88 ± 4.28 kcal/mol) and Meshimakobnol B (-25.86 ± 3.51 kcal/mol) bind similarly to ponatinib (-25.54 ± 6.31 kcal/mol). Per-residue decomposition explored residues MET290, VAL299, ILE315, and PHE359 as crucial for binding to the T315I-BCR::ABL1 mutant protein.
Phellifuropyranone A and Meshimakobnol B show significant potency as inhibitors of the T315I-BCR::ABL1 mutant protein, comparable to ponatinib. These compounds may serve as effective alternatives or synergistic agents with ponatinib, potentially overcoming drug resistance and improving treatment outcomes in Chronic Myeloid Leukemia.
由于T315I BCR::ABL1突变，慢性粒细胞白血病（CML）的治疗极具挑战性。尽管真菌代谢产物因其药物潜力而闻名，但尚无用于CML的获批药物。我们的研究筛选了约2000种真菌次级代谢产物，以发现靶向T315I - BCR::ABL1突变蛋白的抑制剂。
我们进行了全面分析，以阐明T315I - BCR::ABL1突变蛋白与选定真菌代谢产物之间的相互作用。这些分析包括分子对接、ADMET评估、分子动力学模拟、主成分分析、自由能景观探索和残基分解。
我们确定了真菌次级代谢产物的一系列结合亲和力，范围从 - 11.2千卡/摩尔至 - 2.90千卡/摩尔，共结晶的泊那替尼显示出 - 9.9千卡/摩尔的结合亲和力。值得注意的是，27种真菌代谢产物的亲和力≤ - 10.0千卡/摩尔，超过了泊那替尼。包括桑黄呋喃酮A和真柄口醇B在内的8种化合物显示出良好的类药性。分子动力学参数，包括均方根偏差（RMSD）、均方根波动（RMSF）、回旋半径（Rg）和溶剂可及表面积（SASA），证实桑黄呋喃酮A和真柄口醇B与T315I - BCR::ABL1突变蛋白稳定结合。此外，主成分分析、动态相关矩阵分析（DCCM）和自由能景观分析验证了分子动力学参数的一致性。MM/PBSA分析表明，桑黄呋喃酮A（ - 22.88 ± 4.28千卡/摩尔）和真柄口醇B（ - 25.86 ± 3.51千卡/摩尔）与泊那替尼（ - 25.54 ± 6.31千卡/摩尔）的结合方式相似。残基分解研究发现，甲硫氨酸290、缬氨酸299、异亮氨酸315和苯丙氨酸359残基对于与T315I - BCR::ABL1突变蛋白的结合至关重要。
桑黄呋喃酮A和真柄口醇B作为T315I - BCR::ABL1突变蛋白的抑制剂显示出显著效力，与泊那替尼相当。这些化合物可能作为泊那替尼的有效替代品或协同剂，潜在地克服耐药性并改善慢性粒细胞白血病的治疗效果。
