Centre of Excellence in Natural Products and Therapeutics, Department of Biotechnology and Bioinformatics, Sambalpur University, Sambalpur, Odisha, India.
Drug Discovery Research Centre, Translational Health Science and Technology Institute, Pali, Haryana, India.
J Biomol Struct Dyn. 2021 Sep;39(14):5276-5289. doi: 10.1080/07391102.2020.1785945. Epub 2020 Jul 1.
Docetaxel (DOX) based combination therapy is a novel therapeutic strategy that attracts great interest in breast cancer treatment but its clinical utility got limited due to side effects. In contrast, noscapine, an antitussive drug showed antitumor activity against many cancers without any side effects that targets microtubules and attenuates its dynamic instability. In the quest for an increase in the anticancer activity of noscapine, we strategically designed a novel derivative, 9-vinyl phenyl noscapine (VPN), based on our molecular docking and molecular dynamics simulation effort. Molecular docking of VPN and DOX onto microtubule revealed a docking score of -4.82 kcal/mol and -6.67 kcal/mol respectively, while the docking score of VPN was changed to -3.23 kcal/mol when it was docked onto the co-complex of tubulin-DOX. Further, the binding free energy (ΔG) of VPN and DOX with tubulin showed -24.04 and -18.65 kcal/mol respectively, while the binding free energy of DOX was increased further in combination with VPN (ΔG was reduced to -21.41 kcal/mol), denoting combination effect of both ligands. The IC value amounted to 30.17 µM and 19.92 µM for VPN and 0.621 µM and 0.193 µM for DOX, respectively for 48 h and 72 h. The dose dependent cytotoxicity of DOX has been reduced considerably with the combination dose regimen of VPN. Further, the combine effect of both the agents improved the apoptotic cell death 28.5% compared to single agent treatment 5.71% and 10.5% for VPN and DOX, respectively. Both agents bind effectively to tubulin in single and in combination to interfere with cell cycle progression in G2/M transition. This study provides novel concept of combination treatment of DOX and VPN to amend efficiency in breast cancer treatment.Communicated by Ramaswamy H. Sarma.
多西紫杉醇（DOX）为基础的联合治疗是一种新的治疗策略，在乳腺癌治疗中引起了极大的兴趣，但由于副作用，其临床应用受到限制。相比之下，那可丁是一种镇咳药，对许多癌症具有抗肿瘤活性，没有任何副作用，作用靶点是微管，并使其动态不稳定性减弱。在寻求增加那可丁的抗癌活性的过程中，我们根据我们的分子对接和分子动力学模拟工作，设计了一种新型衍生物，9-乙烯基苯基那可丁（VPN）。VPN 和 DOX 与微管的分子对接显示，对接评分分别为-4.82 kcal/mol 和-6.67 kcal/mol，而当 VPN 与 DOX 与微管的共复合物对接时，其对接评分变为-3.23 kcal/mol。此外，VPN 和 DOX 与微管的结合自由能（ΔG）分别为-24.04 和-18.65 kcal/mol，而当与 VPN 结合时，DOX 的结合自由能进一步增加（ΔG 降低至-21.41 kcal/mol），表明两种配体具有组合效应。VPN 的 IC 值分别为 30.17 µM 和 19.92 µM，DOX 的 IC 值分别为 0.621 µM 和 0.193 µM，分别为 48 h 和 72 h。DOX 的剂量依赖性细胞毒性随着 VPN 的组合剂量方案而大大降低。此外，与单一药物治疗相比，两种药物的联合作用将细胞凋亡死亡提高了 28.5%，分别为 VPN 的 5.71%和 DOX 的 10.5%。两种药物均能有效地与微管结合，并在单独和联合作用下干扰细胞周期在 G2/M 期的进展。这项研究提供了 DOX 和 VPN 联合治疗的新概念，以提高乳腺癌治疗的效率。由 Ramaswamy H. Sarma 传达。
