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14种多激酶抑制剂的化学反应性、光学和药代动力学研究及其对ACK1的对接相互作用在精准肿瘤学中的应用

Chemical Reactivity and Optical and Pharmacokinetics Studies of 14 Multikinase Inhibitors and Their Docking Interactions Toward ACK1 for Precision Oncology.

作者信息

Srivastava Ruby

机构信息

CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.

出版信息

Front Chem. 2022 Apr 14;10:843642. doi: 10.3389/fchem.2022.843642. eCollection 2022.

DOI:10.3389/fchem.2022.843642
PMID:35494626
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9050413/
Abstract

Activated Cdc42-associated kinase 1 (ACK1/TNK2) has a significant role in cell endocytosis, survival, proliferation, and migration. Mutations in ACK1 are closely associated with the occurrence and development of cancers. In this work, a conceptual density functional theory (CDFT)-based computational peptidology (CDFT-CP) method is used to study the chemical reactivity of 14 multikinase inhibitors. Optical properties of these inhibitors are studied by time-dependent density functional theory (TDDFT). Various biological and pharmacokinetic parameters are studied by Osiris, Molinspiration, and BOILED-Egg in SwissADME software tools. Physicochemical and biopharmaceutical (PCB), reverse mutation assay (AMES) mutagenicity, toxicity, and risk prediction are estimated by Simulations plus ADMET Predictor 10.2 software. MD simulations for an active model of ACK1 is carried out by the CABS-flex 2.0 web server, and potential binding pockets for ACK1 are searched using the PrankWeb server. SwissTargetPrediction is used to predict the potential targets for the multikinase inhibitors. Docking studies are carried out for ACK1-multikinase inhibitors using Autodock 4.2 software. Noncovalent interactions for ACK1-multikinase inhibitor complexes are studied using the Protein-Ligand Interaction Profiler (PLIP) server. Results indicated higher binding affinities and strong noncovalent interactions in ACK1-multikinase inhibitor complexes.

摘要

活化的Cdc42相关激酶1（ACK1/TNK2）在细胞内吞作用、存活、增殖和迁移中发挥着重要作用。ACK1中的突变与癌症的发生和发展密切相关。在这项工作中，基于概念密度泛函理论（CDFT）的计算肽学（CDFT-CP）方法被用于研究14种多激酶抑制剂的化学反应性。通过含时密度泛函理论（TDDFT）研究这些抑制剂的光学性质。利用瑞士ADME软件工具中的Osiris、Molinspiration和BOILED-Egg研究各种生物学和药代动力学参数。通过Simulations plus ADMET Predictor 10.2软件估计物理化学和生物药剂学（PCB）、回复突变试验（AMES）致突变性、毒性和风险预测。通过CABS-flex 2.0网络服务器对ACK1的活性模型进行分子动力学（MD）模拟，并使用PrankWeb服务器搜索ACK1的潜在结合口袋。使用SwissTargetPrediction预测多激酶抑制剂的潜在靶点。使用Autodock 4.2软件对ACK1-多激酶抑制剂进行对接研究。使用蛋白质-配体相互作用分析器（PLIP）服务器研究ACK1-多激酶抑制剂复合物的非共价相互作用。结果表明ACK1-多激酶抑制剂复合物具有更高的结合亲和力和强烈的非共价相互作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac07/9050413/a6ce448bc89b/fchem-10-843642-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac07/9050413/2ccb33f67402/fchem-10-843642-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac07/9050413/6c3215369822/fchem-10-843642-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac07/9050413/fb29540adbb8/fchem-10-843642-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac07/9050413/a6ce448bc89b/fchem-10-843642-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac07/9050413/2ccb33f67402/fchem-10-843642-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac07/9050413/6c3215369822/fchem-10-843642-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac07/9050413/fb29540adbb8/fchem-10-843642-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac07/9050413/a6ce448bc89b/fchem-10-843642-g004.jpg

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