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作者

Han, Min Sun, Dongdong

作者单位

Department of Obstetrics and Gynaecology, the Fourth People's Hospital of Jinan, Second Affiliated Hospital of Taishan Medical University, 250031, Jinan, China

刊名

Journal of Computer-Aided Molecular Design

年份

2019

卷号

Vol.33 No.7

页码

689-698

ISSN

0920-654X

关键词

Cell viability Cervical cancer Consensus scoring Inhibitory activity Kinase–inhibitor binding profile Molecular docking

摘要

The kinase-regulatory cell signaling networks play a central role in the pathogenesis of human cervical cancer . However, only few kinase inhibitors have been successfully developed for treatment of this cancer to date. Considering that the active sites of protein kinases are highly conserved and small-molecule inhibitors should generally exhibit high promiscuity and broad specificity across the hCC-related kinase array, it is supposed that the established kinase targets of hCC can be targeted u...更多

The kinase-regulatory cell signaling networks play a central role in the pathogenesis of human cervical cancer . However, only few kinase inhibitors have been successfully developed for treatment of this cancer to date. Considering that the active sites of protein kinases are highly conserved and small-molecule inhibitors should generally exhibit high promiscuity and broad specificity across the hCC-related kinase array, it is supposed that the established kinase targets of hCC can be targeted unexpectedly by certain noncognate kinase inhibitors. This provides a novel idea to practice the new uses for old drugs in anti-cancer chemotherapy. Here, we create a systematic kinase–inhibitor binding profile in a high-throughput manner by molecular docking and consensus scoring, where the kinases have been collected as therapeutic targets of hCC and the inhibitors are reversible, ATP-competitive and readily available. The docking/scoring scheme is tested rigorously with structure-solved and affinity-known kinase–inhibitor complex samples, which is later demonstrated to be effective in inferring unexpected inhibitor response to hCC-related kinases. Few promising kinase–inhibitor pairs are identified from the profile and tested experimentally at cellular and molecular levels. It is found that the kinase–inhibitor promiscuity is a common phenomenon but only few can interaction effectively and inhibit potently. In addition, the high-scoring inhibitors generally exhibit good suppressing potency on hCC cell viability as compared to those low-scoring ones, imparting that the created profile can well reflect the tumor cytotoxicity of noncognate kinase inhibitors. A further kinase assay suggests that the ErbB family kinases are the potential targets of these high-scoring inhibitors, with noncognate inhibitory activity up to nanomolar level. Structure analysis reveals that the nonbonded interactions of potent noncogante kinase–inhibitor binding can divided into a polar tail and a nonpolar lobe, which confer specificity and stability to the binding, respectively.收起

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