Mohamed Alkhair Adam Khalil, Asiamah Isaac, Elamin Ghazi, Darkwa James, Adokoh Christian K
Department of Biomedical Sciences, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana.
Department of Chemistry, School of Physical Sciences, College of Agriculture and Natural Sciences, University of Cape Coast, Cape Coast, Ghana.
Front Chem. 2025 Jun 12;13:1533026. doi: 10.3389/fchem.2025.1533026. eCollection 2025.
This study employed in silico methods to investigate the anticancer potential and mechanisms of twenty novel phosphinogold(I) thiocarbohydrate complexes.
Molecular docking and Prime MM-GBSA screening of seventeen cancer-related protein targets, including Human Double Minute 2 protein (HDM2), DNA methyltransferase-1 (DNMT1), Protein Kinase B (AKT2), and Poly (ADP-ribose) polymerase 1 (PARP-1), were conducted. Molecular dynamics simulations were performed for complex .
Virtual screening revealed strong binding affinities for several complexes, often surpassing native ligands. All the complexes except , , and exhibited strong binding affinity with one or two cancer protein targets compared to native ligands. Complex emerged as the best candidate, demonstrating promising binding affinity particularly against AKT2 (-82.40 kcal/mol) and PARP-1 (-75.7 kcal/mol). Molecular dynamics simulations of complex with PARP-1 and AKT2 revealed distinct binding profiles, with a more stable interaction with PARP-1, suggesting its potential for disrupting DNA repair mechanisms. Binuclear complexes generally exhibited higher affinities than mononuclear counterparts, particularly for DNMT1 and HDM2. Complex demonstrated high activity against prostate, colon, and breast cancer cell lines (IC50 = 0.03, 0.25, and 0.07 μM respectively), collaborating with a significant interaction with Human Epidermal Growth Factor Receptor 2 (HER2) (-71.15 kcal/mol binding affinity) . While acetylation decreased binding affinity; it enhanced cellular activity as reported in studies indicative of the need to balance lipophilicity and binding strength in future ligand design.
These findings provide valuable insights into multi-target anticancer mechanisms, with a particular emphasis on complex as a potential PARP-1 inhibitor, and guide future optimization and experimental validation of these novel gold-based complexes. The stable interaction of complex with PARP-1 highlights PARP-1 as a particularly promising therapeutic target. Binuclear complexes' superior affinities for DNMT1 and HDM2 suggest structural advantages for multi-target inhibition.
The paradoxical effect of acetylation underscores the importance of balancing lipophilicity and binding strength in ligand design.
本研究采用计算机模拟方法来研究20种新型膦金（I）硫代碳水化合物配合物的抗癌潜力及作用机制。
对包括人双微体2蛋白（HDM2）、DNA甲基转移酶-1（DNMT1）、蛋白激酶B（AKT2）和聚（ADP-核糖）聚合酶1（PARP-1）在内的17个癌症相关蛋白靶点进行分子对接和Prime MM-GBSA筛选。对复合物进行分子动力学模拟。
虚拟筛选显示几种配合物具有很强的结合亲和力，常常超过天然配体。与天然配体相比，除[具体配合物1]、[具体配合物2]和[具体配合物3]外，所有配合物都与一两个癌症蛋白靶点表现出很强的结合亲和力。配合物[最佳配合物]成为最佳候选物，尤其对AKT2（-82.40千卡/摩尔）和PARP-1（-75.7千卡/摩尔）表现出有前景的结合亲和力。配合物[最佳配合物]与PARP-1和AKT2的分子动力学模拟揭示了不同的结合模式，与PARP-1的相互作用更稳定，表明其具有破坏DNA修复机制的潜力。双核配合物通常比单核配合物表现出更高的亲和力，特别是对DNMT1和HDM2。配合物[具体配合物4]对前列腺癌、结肠癌和乳腺癌细胞系表现出高活性（IC50分别为0.03、0.25和0.07微摩尔），与人类表皮生长因子受体2（HER2）有显著相互作用（结合亲和力为-71.15千卡/摩尔）。虽然乙酰化降低了结合亲和力；但如[相关研究]报道，它增强了细胞活性，这表明在未来的配体设计中需要平衡亲脂性和结合强度。
这些发现为多靶点抗癌机制提供了有价值的见解，特别强调配合物[最佳配合物]作为潜在PARP-1抑制剂的作用，并指导这些新型金基配合物的未来优化和实验验证。配合物[最佳配合物]与PARP-1的稳定相互作用突出了PARP-1作为一个特别有前景的治疗靶点。双核配合物对DNMT1和HDM2的优越亲和力表明其在多靶点抑制方面的结构优势。
乙酰化的矛盾效应强调了在配体设计中平衡亲脂性和结合强度的重要性。
