Systematic Profiling and Evaluation of Structure-based Kinase–Inhibitor Interactome in Cervical Cancer by Integrating In Silico Analyses and In Vitro Assays at Molecular and Cellular Levels

Zhu, Lixia; Liu, Qin; Hua, Ya-Fang; Yang, Ning; Zhang, Xuegang; Ding, Xi

doi:10.1016/j.compbiolchem.2019.04.016

Computational Biology and Chemistry

2019

DOI: 10.1016/j.compbiolchem.2019.04.016

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Systematic Profiling and Evaluation of Structure-based Kinase–Inhibitor Interactome in Cervical Cancer by Integrating In Silico Analyses and In Vitro Assays at Molecular and Cellular Levels

Lixia Zhu

Qin Liu

Ya-Fang Hua

et al.

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Cited by 5 publications

References 66 publications

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Integrated in silico‐in vitro profiling of the systematic response of paclitaxel and its analogues to clinical tubulin variations in gynecologic cancers: Implications for the molecular mechanism of acquired tumor chemoresistance

Lu,

Shen,

Zhao

2024

J Chinese Chemical Soc

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Tubulin is the basic building block of microtubule and has been established as a druggable target of various cancers. However, a large number of somatic missense variations have been clinically observed to harbor in the tubulin protein, which can cause drug resistance to microtubule‐stabilizing agents (MSAs), thus largely limiting the applications of MSAs in tumor chemotherapy. In this study, we created a systematic response profile of (PTX), the first approved MSA, as well as its diverse analogues (we herein termed paclitogues [PLGs]), to various tubulin variations by using an integrated in silico‐in vitro (iSiV) strategy. These PLGs share a similar action mechanism and the same binding pocket with PTX, while these variations were enriched from the gene ontology (GO) network involving a variety of gynecologic cancers (GCs). A considerable difference between the ligand response profiles to α‐ and β‐tubulin variations was observed; the former commonly has only marginal and even effects, whereas the latter generally exhibits significant but dramatically changeable responses. A number of resistant variations and few sensitive variations were identified from the profile; they can considerably reduce PTX affinity by up to ~30‐fold or moderately improve the affinity by <5‐fold. Multiple resistant variations can co‐work in a single tubulin variant to further combat with the PTX ligand. By examining their locations in the structural architecture of tubulin protein, it is revealed that resistant variations occur either in MSA‐binding pocket to directly block ligand binding or out of the pocket to indirectly impair the binding through a long‐range conformational effect, while the sensitive variations promote the binding by forming additional noncovalent interactions with ligand.

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Integrated in silico‐in vitro profiling of the systematic response of paclitaxel and its analogues to clinical tubulin variations in gynecologic cancers: Implications for the molecular mechanism of acquired tumor chemoresistance

Lu,

Shen,

Zhao

2024

J Chinese Chemical Soc

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Inverse in silico–in vitro fishing of unexpected paroxetine kinase targets from tumor druggable kinome

2020

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Rational creation and systematic analysis of cervical cancer kinase–inhibitor binding profile

Han

Dongdong

2019

J Comput Aided Mol Des

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Systematic Profiling and Evaluation of Structure-based Kinase–Inhibitor Interactome in Cervical Cancer by Integrating In Silico Analyses and In Vitro Assays at Molecular and Cellular Levels

Cited by 5 publications

References 66 publications

Integrated in silico‐in vitro profiling of the systematic response of paclitaxel and its analogues to clinical tubulin variations in gynecologic cancers: Implications for the molecular mechanism of acquired tumor chemoresistance

Integrated in silico‐in vitro profiling of the systematic response of paclitaxel and its analogues to clinical tubulin variations in gynecologic cancers: Implications for the molecular mechanism of acquired tumor chemoresistance

Inverse in silico–in vitro fishing of unexpected paroxetine kinase targets from tumor druggable kinome

Rational creation and systematic analysis of cervical cancer kinase–inhibitor binding profile

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