Marine Compound-Carpatamide D as a Potential Inhibitor Against TOP2A and Its Mutant D1021Y in Colorectal Cancer: Insights from DFT, MEP and Molecular Dynamics Simulation

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS ACS Applied Bio Materials Pub Date : 2024-09-12 DOI:10.1007/s12033-024-01265-9

P. Priyamvada, Gayathri Ashok, Shalini Mathpal, Anand Anbarasu, Sudha Ramaiah

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Abstract

Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, hence there is an urgent need for new and effective therapeutic options. DNA topoisomerase 2A (TOP2A) plays a crucial role in the cell cycle and is involved in CRC progression, making it essential to identify structural and functional relevant alterations. Among the 24 mutations, our findings indicated that mutation D1021Y has the most deleterious effect on the TOP2A protein. Based on virtual screening of 31,561 compounds, we identified three lead candidates: 17683 (nigrospoxydon C), 28461 (carpatamide D), and 28853 (6′-O-acetyl-isohomaarbutin), which showed promising inhibitory effect against TOP2A and its mutant form. These compounds were assessed for their stability using density functional theory (DFT) analysis, where carpatamide D possessed the least energy gap of 4.398 eV showing its high reactivity among all. Further, molecular docking also shows the carpatamide D as the top candidate, which exhibited favourable docking energy against the TOP2A wild type (− 7.47 kcal/mol) and with D1021Y mutant (− 7.62 kcal/mol) as compared to reference compound PK1, which showed − 6.11 kcal/mol TOP2A wild type and − 6.24 kcal/mol against mutant type. The molecular dynamics simulation was performed to analyse the dynamics and stability of complex, which revealed TOP2A_28641 and D1021Y_28641 complexes to be stable with least root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF). Molecular mechanics/Poisson–Boltzmann surface area calculations indicated that TOP2A_28641 and D1021Y_28641 complexes exhibited the lowest binding energy of − 23.55 kcal/mol and − 25.03 kcal/mol, respectively. Our findings suggest carpatamide D as a promising lead compound for the TOP2A_D1021Y targeted cancer therapies, which needs further experimental validation.

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海洋化合物-卡帕酰胺 D 作为结直肠癌 TOP2A 及其突变体 D1021Y 的潜在抑制剂：从 DFT、MEP 和分子动力学模拟中获得的启示

摘要大肠癌（CRC）是全球发病率第三高的癌症，因此迫切需要新的有效治疗方案。DNA 拓扑异构酶 2A（TOP2A）在细胞周期中起着至关重要的作用，并参与 CRC 的进展，因此确定相关的结构和功能改变至关重要。我们的研究结果表明，在 24 个突变中，D1021Y 突变对 TOP2A 蛋白的有害影响最大。基于对 31,561 种化合物的虚拟筛选，我们确定了三种先导候选化合物：17683（nigrospoxydon C）、28461（carpatamide D）和28853（6′-O-乙酰基-isohomaarbutin）。利用密度泛函理论（DFT）分析评估了这些化合物的稳定性，其中卡帕酰胺 D 的能隙最小，为 4.398 eV，表明其在所有化合物中具有较高的反应活性。此外，分子对接也显示出卡帕酰胺 D 是最理想的候选化合物，它与 TOP2A 野生型（- 7.47 kcal/mol）和 D1021Y 突变型（- 7.62 kcal/mol）的对接能量均优于参考化合物 PK1，后者与 TOP2A 野生型的对接能量为 - 6.11 kcal/mol，与突变型的对接能量为 - 6.24 kcal/mol。分子动力学模拟分析了复合物的动力学和稳定性，结果表明 TOP2A_28641 和 D1021Y_28641 复合物是稳定的，均方根偏差（RMSD）和均方根波动（RMSF）最小。分子力学/泊松-波尔兹曼表面积计算表明，TOP2A_28641 和 D1021Y_28641 复合物的结合能最低，分别为 - 23.55 kcal/mol 和 - 25.03 kcal/mol。我们的研究结果表明，卡帕酰胺 D 是一种很有前景的 TOP2A_D1021Y 癌症靶向治疗先导化合物，还需要进一步的实验验证。

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