Colchicine site inhibitors are microtubule destabilizers having promising role in cancer therapeutics. In the current study, four such indanone derivatives (t1, t9, t14 and t17) with 3,4,5-trimethoxyphenyl fragment (ring A) and showing significant microtubule destabilization property have been explored. The interaction mechanism and conformational modes triggered by binding of these indanone derivatives and combretastatin at colchicine binding site (CBS) of αβ-tubulin dimer were studied using molecular dynamics (MD) simulation, principle component analysis and free energy landscape analysis. In the MD results, t1 showed binding similar to colchicine interacting in the deep hydrophobic core at the CBS. While t9, t14 and t17 showed binding conformation similar to combretastatin, with ring A superficially binding at the CBS. Results demonstrated that ring A played a vital role in binding via hydrophobic interactions and got anchored between the S8 and S9 sheets, H8 helix and T7 loop at the CBS. Conformational modes study revealed that twisting and bending conformational motions (as found in the apo system) were nearly absent in the ligand bound systems. Absence of twisting motion might causes loss of lateral contacts in microtubule, thus promoting microtubule destabilization. This study provides detailed account of microtubule destabilization mechanism by indanone ligands and combretastatin, and would be helpful for designing microtubule destabilizers with higher activity.

中文翻译：

---

使用分子动力学模拟和构象模式分析洞察3,4,5-三甲氧基苯基茚满酮衍生物的微管去稳定机理。

秋水仙碱位点抑制剂是在癌症治疗中具有有希望作用的微管去稳定剂。在当前的研究中，已经研究了具有3,4,5-三甲氧基苯基片段（环A）并显示出显着的微管去稳定特性的四个这样的茚满酮衍生物（t1，t9，t14和t17）。利用分子动力学（MD）模拟，主成分分析和自由能态分析，研究了茚满酮衍生物与康维他汀在αβ-微管蛋白二聚体秋水仙碱结合位点（CBS）的结合所引发的相互作用机理和构象模式。在MD结果中，t1显示出类似于秋水仙碱在CBS深疏水核心中相互作用的结合。而t9，t14和t17表现出类似于康普他汀的结合构象，环A在CBS表面结合。结果表明，环A通过疏水相互作用在结合中起着至关重要的作用，并被固定在C8的S8和S9薄片，H8螺旋和T7环之间。构象模式研究表明，在配体结合系统中几乎没有扭曲和弯曲的构象运动（如在载脂蛋白系统中发现的）。缺乏扭转运动可能会导致微管中的侧向接触丧失，从而促进微管的不稳定。这项研究提供了茚满酮配体和康他汀抑制微管去稳定机理的详细说明，将有助于设计具有更高活性的微管去稳定剂。构象模式研究表明，在配体结合系统中几乎没有扭曲和弯曲的构象运动（如在apo系统中发现的）。缺乏扭转运动可能会导致微管中的侧向接触丧失，从而促进微管的不稳定。这项研究提供了茚满酮配体和康他汀抑制微管去稳定机理的详细说明，将有助于设计具有更高活性的微管去稳定剂。构象模式研究表明，在配体结合系统中几乎没有扭曲和弯曲的构象运动（如在apo系统中发现的）。缺乏扭转运动可能会导致微管中的侧向接触丧失，从而促进微管的不稳定。这项研究提供了茚满酮配体和康他汀抑制微管去稳定机理的详细说明，将有助于设计具有更高活性的微管去稳定剂。