Department of Biotechnology, Era's Lucknow Medical College & Hospital, Era University, Sarfarazganj, Hardoi Road, Lucknow 226003, India.
Department of Chemistry, Era University, Sarfarazganj, Hardoi Road, Lucknow 226003, India.
Molecules. 2023 Aug 3;28(15):5853. doi: 10.3390/molecules28155853.
Polo-like kinase-1 (PLK-1) is an essential mitotic serine/threonine (Ser/Thr) kinase that belongs to the Polo-like kinase (PLK) family and is overexpressed in non-small cell lung cancer (NSCLC) via promotion of cell division. Therefore, PLK-1 may act as a promising target for the therapeutic cure of various cancers. Although a variety of anti-cancer drugs, both synthetic and naturally occurring, such as volasertib, onvansertib, thymoquinone, and quercetin, are available either alone or in combination with other therapies, they have limited efficacy, especially in the advanced stages of cancer. To the best of our knowledge, no anticancer agent has been reported from marine algae or microorganisms to date. Thus, the aim of the present study is a high-throughput virtual screening of phlorotannins, obtained from edible brown algae, using molecular docking and molecular dynamic simulation analysis. Among these, Pentafuhalol-B (PtB) showed the lowest binding energy (best of triplicate runs) against the target protein PLK-1 as compared to the reference drug volasertib. Further, in MD simulation (best of triplicate runs), the PtB-PLK-1 complex displayed stability in an implicit water system through the formation of strong molecular interactions. Additionally, MMGBSA calculation (best of triplicate runs) was also performed to validate the PtB-PLK-1 complex binding affinities and stability. Moreover, the chemical reactivity of PtB towards the PLK-1 target was also optimised using density functional theory (DFT) calculations, which exhibited a lower HOMO-LUMO energy gap. Overall, these studies suggest that PtB binds strongly within the pocket sites of PLK-1 through the formation of a stable complex, and also shows higher chemical reactivity than the reference drug volasertib. The present study demonstrated the inhibitory nature of PtB against the PLK-1 protein, establishing its potential usefulness as a small molecule inhibitor for the treatment of different types of cancer.
丝氨酸/苏氨酸（Ser/Thr）激酶 Polo 样激酶-1（PLK-1）是一种必需的有丝分裂激酶，属于 Polo 样激酶（PLK）家族，通过促进细胞分裂在非小细胞肺癌（NSCLC）中过表达。因此，PLK-1 可能成为治疗各种癌症的有前途的靶点。尽管有多种抗癌药物，包括合成和天然的，如 volasertib、onvansertib、thymoquinone 和 quercetin，无论是单独使用还是与其他疗法联合使用，都具有有限的疗效，特别是在癌症的晚期。据我们所知，到目前为止，还没有从海洋藻类或微生物中报道过抗癌剂。因此，本研究的目的是使用分子对接和分子动力学模拟分析对从食用褐藻中获得的 phlorotannins 进行高通量虚拟筛选。在这些化合物中，Pentafuhalol-B（PtB）与参比药物 volasertib 相比，对靶蛋白 PLK-1 的结合能最低（三次重复运行中的最佳值）。此外，在 MD 模拟（三次重复运行中的最佳值）中，PtB-PLK-1 复合物通过形成强分子相互作用在包含水环境中显示出稳定性。此外，还进行了 MMGBSA 计算（三次重复运行中的最佳值），以验证 PtB-PLK-1 复合物的结合亲和力和稳定性。此外，还使用密度泛函理论（DFT）计算优化了 PtB 对 PLK-1 靶标的化学反应性，结果显示其 HOMO-LUMO 能隙较低。总的来说，这些研究表明 PtB 通过形成稳定的复合物与 PLK-1 口袋部位强烈结合，并且显示出比参比药物 volasertib 更高的化学反应性。本研究证明了 PtB 对 PLK-1 蛋白的抑制作用，确立了其作为治疗不同类型癌症的小分子抑制剂的潜在用途。
