Computational benchmarking of putative KIFC1 inhibitors
Computational benchmarking of putative KIFC1 inhibitors
复制标题
DOI：
10.1002/med.21926
复制
发表时间：
2022-09
影响因子：
13.3
通讯作者：
Nivya Sharma;Dani Setiawan;D. Hamelberg;Rishikesh Narayan;R. Aneja
中科院分区：
文献类型：
--
作者：
Nivya Sharma;Dani Setiawan;D. Hamelberg;Rishikesh Narayan;R. Aneja
动物细胞中的中心体在纺锤体极形成、成核、细胞分裂过程中微管的正确排列以及每个子细胞中染色体的分布中发挥着重要作用。中心体扩增涉及中心体的结构和数量异常，可导致染色体不稳定和细胞周期失调，导致癌症的发展和转移。然而，中心体扩增引起的干扰也会通过激活有丝分裂检查点和促进有丝分裂灾难来限制癌细胞的存活。作为一种聪明的逃避方式，癌细胞将多余的中心体聚集成伪双极纺锤体，并在细胞周期中前进。这种现象被称为中心体聚集（CC），涉及许多蛋白质，并且作为一种特定的癌细胞靶向武器而引起了相当大的关注。驱动蛋白-14 运动蛋白 KIFC1 是一种参与 CC 的负端定向运动蛋白。由于 KIFC1 在各种癌症中上调并调节致癌信号级联，因此它已成为潜在的化疗靶点。许多分子因其在癌细胞中的中心体去簇活性而被鉴定为 KIFC1 抑制剂。尽管该领域的文献不断增加，但很少有人努力回顾其进展。本综述旨在整理并深入分析已知的 KIFC1 抑制剂及其生物活性。此外，我们还提供了假定的 KIFC1 抑制剂及其结合位点和结合亲和力的计算对接数据。这种首次比较分析涉及不同 KIFC1 抑制剂的实验生物学、化学和计算对接，可能有助于指导有效抑制剂的选择和设计决策。
The centrosome in animal cells is instrumental in spindle pole formation, nucleation, proper alignment of microtubules during cell division, and distribution of chromosomes in each daughter cell. Centrosome amplification involving structural and numerical abnormalities in the centrosome can cause chromosomal instability and dysregulation of the cell cycle, leading to cancer development and metastasis. However, disturbances caused by centrosome amplification can also limit cancer cell survival by activating mitotic checkpoints and promoting mitotic catastrophe. As a smart escape, cancer cells cluster their surplus of centrosomes into pseudo‐bipolar spindles and progress through the cell cycle. This phenomenon, known as centrosome clustering (CC), involves many proteins and has garnered considerable attention as a specific cancer cell‐targeting weapon. The kinesin‐14 motor protein KIFC1 is a minus end‐directed motor protein that is involved in CC. Because KIFC1 is upregulated in various cancers and modulates oncogenic signaling cascades, it has emerged as a potential chemotherapeutic target. Many molecules have been identified as KIFC1 inhibitors because of their centrosome declustering activity in cancer cells. Despite the ever‐increasing literature in this field, there have been few efforts to review the progress. The current review aims to collate and present an in‐depth analysis of known KIFC1 inhibitors and their biological activities. Additionally, we present computational docking data of putative KIFC1 inhibitors with their binding sites and binding affinities. This first‐of‐kind comparative analysis involving experimental biology, chemistry, and computational docking of different KIFC1 inhibitors may help guide decision‐making in the selection and design of potent inhibitors.