Department of Chemistry, Indian Institute of Technology, Guwahati Assam, 781039, India.
Phys Chem Chem Phys. 2021 Feb 7;23(5):3361-3376. doi: 10.1039/d0cp05210h. Epub 2021 Jan 27.
The stability of c-KIT G-quadruplex DNA via ligands has been a significant concern in the growing field of cancer therapy. Thus, it is very important to understand the mechanism behind the high binding affinity of the small drug molecules on the c-KIT G-quadruplex DNA. In this study, we have investigated the binding mode and pathway of the APTO-253 ligand on the c-KIT G-quadruplex DNA employing a total of 10 μs all atom molecular dynamics simulations and further 8.82 μs simulations via the umbrella sampling method using both OL15 and BSC1 latest force fields for DNA structures. From the cluster structure analysis, mainly three binding pathways i.e., top, bottom and side loop stacking modes are identified. Moreover, RMSD, RMSF and 2D-RMSD values indicate that the c-KIT G-quadruplex DNA and APTO-253 molecules are stable throughout the simulation run. Furthermore, the number of hydrogen bonds in each tetrad and the distance between the two central K cations confirm that the c-KIT G-quadruplex DNA maintains its conformation in the process of complex formation with the APTO-253 ligand. The binding free energies and the minimum values in the potential of mean forces suggest that the binding processes are energetically favorable. Furthermore, we have found that the bottom stacking mode is the most favorable binding mode among all the three modes for the OL15 force field. However, for the BSC1 force field, both the top and bottom binding modes of the APTO-253 ligand in c-KIT G-quadruplex DNA are comparable to each other. To investigate the driving force for the complex formation, we have noticed that the van der Waals (vdW) and π-π stacking interactions are mainly responsible. Our detailed studies provide useful information for the discovery of novel drugs in the field of stabilization of G-quadruplex DNAs.
通过配体稳定 c-KIT G-四链体 DNA 一直是癌症治疗领域日益关注的问题。因此，了解小分子药物与 c-KIT G-四链体 DNA 高结合亲和力背后的机制非常重要。在这项研究中，我们通过总共 10μs 的全原子分子动力学模拟和进一步的 8.82μs 的 umbrella sampling 模拟，使用最新的 OL15 和 BSC1 力场研究了 APTO-253 配体在 c-KIT G-四链体 DNA 上的结合模式和途径。从聚类结构分析中，确定了主要的三种结合途径，即顶部、底部和侧环堆积模式。此外，RMSD、RMSF 和 2D-RMSD 值表明，c-KIT G-四链体 DNA 和 APTO-253 分子在整个模拟过程中都是稳定的。此外，每个四联体中的氢键数量和两个中心 K 阳离子之间的距离证实了 c-KIT G-四链体 DNA 在与 APTO-253 配体形成复合物的过程中保持其构象。结合自由能和平均力势能中的最小值表明，结合过程在能量上是有利的。此外，我们发现对于 OL15 力场，在三种模式中，底部堆积模式是最有利的结合模式。然而，对于 BSC1 力场，APTO-253 配体在 c-KIT G-四链体 DNA 中的顶部和底部结合模式彼此相当。为了研究复合物形成的驱动力，我们注意到范德华（vdW）和π-π堆积相互作用主要起作用。我们的详细研究为在 G-四链体 DNA 稳定化领域发现新型药物提供了有用的信息。
