Ghosh Arabinda, Mukerjee Nobendu, Sharma Bhavdeep, Pant Anushree, Kishore Mohanta Yugal, Jawarkar Rahul D, Bakal Ravindrakumar L, Terefe Ermias Mergia, Batiha Gaber El-Saber, Mostafa-Hedeab Gomaa, Aref Albezrah Nisreen Khalid, Dey Abhijit, Baishya Debabrat
Microbiology Division, Department of Botany, Gauhati University, Guwahati, India.
Department of Microbiology, Ramakrishna Mission Vivekananda Centenary College, Kolkata, India.
Front Pharmacol. 2022 Mar 8;12:812565. doi: 10.3389/fphar.2021.812565. eCollection 2021.
The fact that viruses cause human cancer dates back to the early 1980s. By reprogramming cellular signaling pathways, viruses encoded protein that can regulate altered control of cell cycle events. Viruses can interact with a superfamily of membrane bound protein, receptor tyrosine kinase to modulate their activity in order to increase virus entrance into cells and promotion of viral replication within the host. Therefore, our study aimed at screening of inhibitors of tyrosine kinase using natural compounds from olive. Protein tyrosine kinase (PTK) is an important factor for cancer progression and can be linked to coronavirus. It is evident that over expression of Protein tyrosine kinase (PTK) enhance viral endocytosis and proliferation and the use of tyrosine kinase inhibitors reduced the period of infection period. Functional network studies were carried out using two major PTKs viz. Anaplastic lymphoma kinase (ALK) and B-lymphocytic kinase (BTK). They are associated with coronavirus in regulation of cell signaling proteins for cellular processes. We virtually screened for 161 library of natural compounds from olive found overexpressed in ALK and BTK in metastatic as well as virus host cells. We have employed both ligand and target-based approach for drug designing by high throughput screening using Multilinear regression model based QSAR and docking. The QSAR based virtual screening of 161 olive nutraceutical compounds has successfully identified certain new hit; Wedelosin, in which, the descriptor rsa (ratio of molecular surface area to the solvent accessible surface area) plays crucial role in deciding Wedelosin's inhibitory potency. The best-docked olive nutraceuticals further investigated for the stability and effectivity of the BTK and ALK during in 150 ns molecular dynamics and simulation. Post simulation analysis and binding energy estimation in MMGBSA further revealed the intensive potential of the olive nutraceuticals in PTK inhibition. This study is therefore expected to widen the use of nutraceuticals from olive in cancer as well as SARS-CoV2 alternative therapy.
病毒导致人类癌症这一事实可追溯到20世纪80年代初。通过重新编程细胞信号通路，病毒编码的蛋白质可以调节细胞周期事件的改变控制。病毒可以与膜结合蛋白的一个超家族——受体酪氨酸激酶相互作用，以调节其活性，从而增加病毒进入细胞的机会并促进病毒在宿主体内的复制。因此，我们的研究旨在使用来自橄榄的天然化合物筛选酪氨酸激酶抑制剂。蛋白酪氨酸激酶（PTK）是癌症进展的一个重要因素，并且可能与冠状病毒有关。很明显，蛋白酪氨酸激酶（PTK）的过度表达会增强病毒的内吞作用和增殖，而使用酪氨酸激酶抑制剂可以缩短感染期。使用两种主要的PTK，即间变性淋巴瘤激酶（ALK）和B淋巴细胞激酶（BTK）进行了功能网络研究。它们在调节细胞信号蛋白以参与细胞过程中与冠状病毒有关。我们对在转移性以及病毒宿主细胞中ALK和BTK中过表达的161种橄榄天然化合物文库进行了虚拟筛选。我们采用了基于配体和基于靶点的方法，通过使用基于多线性回归模型的QSAR和对接进行高通量筛选来进行药物设计。对161种橄榄营养化合物进行的基于QSAR的虚拟筛选成功鉴定出了某些新的命中物；wedelosin，其中，描述符rsa（分子表面积与溶剂可及表面积之比）在决定wedelosin的抑制效力中起关键作用。对对接效果最佳的橄榄营养化合物进一步研究了其在150纳秒分子动力学和模拟过程中对BTK和ALK的稳定性和有效性。MMGBSA中的模拟后分析和结合能估计进一步揭示了橄榄营养化合物在抑制PTK方面的巨大潜力。因此，预计这项研究将扩大橄榄营养化合物在癌症以及SARS-CoV2替代疗法中的应用。
