Division of Experimental Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada.
Chem Biol Drug Des. 2011 Oct;78(4):535-46. doi: 10.1111/j.1747-0285.2011.01189.x. Epub 2011 Sep 6.
Noscapine, the benzylisoquinoline alkaloid, 5-(4,5-Dimethoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-6-ium, has been extensively used as a cough-suppressing medication with low toxicity. It has been recently shown to also have anti-cancer activity in mice and humans. In this work, using in silico analyses, the most probable binding site for noscapine is identified to be at the intradimer region of the α and β subunits of the tubulin heterodimer. By utilization of small molecule docking techniques, and an analysis of the thermodynamically favorable binding modes of noscapine in its binding site, the key residues of tubulin monomers interacting with noscapine are determined. Upon noscapine binding, the conformational change in the tubulin heterodimer along with a potential long-range allosteric effect on both the N and E sites is studied by means of molecular dynamics simulations. Noscapine is found to function as a tubulin-stabilizing agent that interacts strongest with the lateral and longitudinal segments of the tubulin dimer, impacting the interaction between monomers in neighboring protofilaments. We infer that this may act as a depolymerization inhibitor of microtubules. As a result of this study, we have designed novel analogues of noscapine with the ultimate goal of finding agents with increased anti-tumor activity and lower inhibitory concentrations than that of noscapine.
北美黄连碱，一种苯并异喹啉生物碱，5-(4,5-二甲氧基-3-氧代-1,3-二氢异苯并呋喃-1-基)-4-甲氧基-6-甲基-5,6,7,8-四氢-[1,3]二氧代[4,5-g]异喹啉-6-鎓，已被广泛用作具有低毒性的镇咳药物。最近的研究表明，它在小鼠和人类中也具有抗癌活性。在这项工作中，通过计算机模拟分析，确定北美黄连碱最可能的结合部位是微管蛋白异二聚体的α和β亚基的二聚体内部区域。通过利用小分子对接技术，并对北美黄连碱在其结合部位的热力学有利结合模式进行分析，确定了与北美黄连碱相互作用的微管蛋白单体的关键残基。在北美黄连碱结合后，通过分子动力学模拟研究了微管蛋白异二聚体的构象变化以及对 N 和 E 位点的潜在远程变构效应。研究发现，北美黄连碱作为一种微管蛋白稳定剂，与微管蛋白二聚体的横向和纵向片段相互作用最强，影响相邻原纤维中单体之间的相互作用。我们推断，这可能是微管解聚抑制剂。通过这项研究，我们设计了北美黄连碱的新型类似物，最终目标是找到具有比北美黄连碱更高的抗肿瘤活性和更低的抑制浓度的药物。
