通过 3D-QSAR 和分子对接研究开发新型 ROCK 抑制剂:多靶点药物设计框架。

IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pharmaceutics Pub Date : 2024-09-26 DOI:10.3390/pharmaceutics16101250
Milan Beljkas, Milos Petkovic, Ana Vuletic, Ana Djuric, Juan Francisco Santibanez, Tatjana Srdic-Rajic, Katarina Nikolic, Slavica Oljacic
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引用次数: 0

摘要

背景/目的:肌动蛋白细胞骨架的改变与肿瘤进展相关,并影响粘附、迁移和侵袭等关键细胞过程。Rho相关含线圈蛋白激酶(ROCK1和ROCK2)是肌动蛋白细胞骨架的重要调节因子,在各种恶性肿瘤中经常过度表达。因此,本研究旨在利用计算机辅助药物设计(CADD)方法确定 ROCK1/ROCK2 抑制剂的关键结构特征。此外,新开发的 ROCK 抑制剂为开发多靶点疗法-ROCK/HDAC(组蛋白去乙酰化酶)多靶点抑制剂提供了重要框架。方法:采用三维-QSAR(定量结构-活性关系研究)和分子对接研究来确定与 ROCK 抑制作用正相关的关键结构特征。采用 MDA-MB-231、HCC1937、Panc-1 和 Mia PaCa-2 细胞评估合成化合物的抗癌特性。结果C-19 显示出了强大的抗癌特性,尤其是在胰腺癌细胞系中增强了细胞凋亡和细胞周期调控。此外,C-19 和 C-22 还显示出与著名的 ROCK 抑制剂法舒地尔相当的强效抗迁移和抗侵袭作用。结论:根据这项研究的结果,我们提出了一种新的多靶点方法,重点是根据 C-19 和 C-22 的结构开发 HDAC/ROCK 双抑制剂,利用这两种信号通路的协同潜力来提高对转移性肿瘤的疗效。我们的研究结果强调了多靶点 ROCK 抑制剂作为未来癌症疗法基础的潜力。
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Development of Novel ROCK Inhibitors via 3D-QSAR and Molecular Docking Studies: A Framework for Multi-Target Drug Design.

Background/Objectives: Alterations in the actin cytoskeleton correlates to tumor progression and affect critical cellular processes such as adhesion, migration and invasion. Rho-associated coiled-coil-containing protein kinases (ROCK1 and ROCK2), important regulators of the actin cytoskeleton, are frequently overexpressed in various malignancies. The aim of this study was therefore to identify the key structural features of ROCK1/ROCK2 inhibitors using computer-aided drug design (CADD) approaches. In addition, new developed ROCK inhibitors provided a significant framework for the development of multitarget therapeutics-ROCK/HDAC (histone deacetylases) multitarget inhibitors. Methods: 3D-QSAR (Quantitative structure-activity relationship study) and molecular docking study were employed in order to identify key structural features that positively correlate with ROCK inhibition. MDA-MB-231, HCC1937, Panc-1 and Mia PaCa-2 cells were used for evaluation of anticancer properties of synthesized compounds. Results: C-19 showed potent anti-cancer properties, especially enhancement of apoptosis and cell cycle modulation in pancreatic cancer cell lines. In addition, C-19 and C-22 showed potent anti-migratory and anti-invasive effects comparable to the well-known ROCK inhibitor fasudil. Conclusions: In light of the results of this study, we propose a novel multi-target approach focusing on developing dual HDAC/ROCK inhibitors based on the structure of both C-19 and C-22, exploiting the synergistic potential of these two signaling pathways to improve therapeutic efficacy in metastatic tumors. Our results emphasize the potential of multi-target ROCK inhibitors as a basis for future cancer therapies.

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来源期刊
Pharmaceutics
Pharmaceutics Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍: Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications,  and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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