Discovery of novel TrkA allosteric inhibitors: Structure-based virtual screening, biological evaluation and preliminary SAR studies

Casein kinase II (CK2) is considered as an attractive cancer therapeutic target, and recent efforts have been made to develop its ATP-competitive inhibitors. However, achieving selectivity with respect to related kinases remains challenging due to the highly conserved ATP-binding pocket of kinases. Allosteric inhibitors, by targeting the much more diversified allosteric site relative to the highly conserved ATP-binding pocket, might be a promising strategy with the enhanced selectivity and reduced toxicity than ATP-competitive inhibitors. The previous studies have highlighted the traditional serendipitousity of discovering allosteric inhibitors owing to the complicate allosteric modulation. In this current study, we identified the novel allosteric inhibitors of CK2α by combing structure-based virtual screening and biological evaluation methods. The structure-based pharmacophore model was built based on the crystal structure of CK2α-compound 15 complex. The ChemBridge fragment library was searched by evaluating the fit values of these molecules with the optimized pharmacophore model, as well as the binding affinity of the CK2α-ligand complexes predicted by Alloscore web server. Six hits forming the holistic interaction mechanism with the αD pocket were retained after pharmacophore- and Alloscore-based screening for biological test. Compound 3 was found to be the most potent non-ATP competitive CK2α inhibitor (IC50 = 13.0 μM) with the anti-proliferative activity on A549 cancer cells (IC50 = 23.1 μM). Our results provide new clues for further development of CK2 allosteric inhibitors as anti-cancer hits.

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Structure Activity Relationship of Arylidene Pyrrolo and Pyrido [2,1-b] Quinazolones as Cytotoxic Agents: Synthesis, SAR Studies, Biological Evaluation and Docking Studies

Medicinal Chemistry ◽

10.2174/1573406411309050003 ◽

2013 ◽

Vol 9 (5) ◽

pp. 642-650 ◽

Cited By ~ 3

Author(s):

Veenu Mangla ◽

Kunal Nepali ◽

Gagandip Singh ◽

Jagjeet Singh ◽

Santosh Guru ◽

...

Keyword(s):

Structure Activity Relationship ◽

Docking Studies ◽

Biological Evaluation ◽

Cytotoxic Agents ◽

Activity Relationship ◽

Sar Studies ◽

Structure Activity ◽

Relationship Of

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Identification of novel insect β-N-acetylhexosaminidase OfHex1 inhibitors based on virtual screening, biological evaluation, and molecular dynamics simulation

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2020.1743758 ◽

2020 ◽

pp. 1-9

Author(s):

Lili Dong ◽

Shengqiang Shen ◽

Yefei Xu ◽

Leng Wang ◽

Qing Yang ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Virtual Screening ◽

Biological Evaluation ◽

Dynamics Simulation

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Discovery of novel Staphylococcus aureus penicillin binding protein 2a inhibitors by multistep virtual screening and biological evaluation

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2021.128001 ◽

2021 ◽

pp. 128001

Author(s):

Na Lv ◽

Qinxiang Kong ◽

Hui Zhang ◽

Jiabin Li

Keyword(s):

Staphylococcus Aureus ◽

Virtual Screening ◽

Binding Protein ◽

Biological Evaluation ◽

Penicillin Binding Protein

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Structure-Based Virtual Screening and Biological Evaluation of Peptide Inhibitors for Polo-Box Domain

Molecules ◽

10.3390/molecules25010107 ◽

2019 ◽

Vol 25 (1) ◽

pp. 107 ◽

Cited By ~ 1

Author(s):

Fang Yan ◽

Guangmei Liu ◽

Tingting Chen ◽

Xiaochen Fu ◽

Miao-Miao Niu

Keyword(s):

Cell Cycle ◽

Virtual Screening ◽

Fold Increase ◽

Pharmacophore Modeling ◽

Biological Evaluation ◽

Peptide Inhibitors ◽

Regulatory Proteins ◽

Competitive Binding Assay ◽

M Phase ◽

Cell Cycle Regulatory Proteins

The polo-box domain of polo-like kinase 1 (PLK1-PBD) is proved to have crucial roles in cell proliferation. Designing PLK1-PBD inhibitors is challenging due to their poor cellular penetration. In this study, we applied a virtual screening workflow based on a combination of structure-based pharmacophore modeling with molecular docking screening techniques, so as to discover potent PLK1-PBD peptide inhibitors. The resulting 9 virtual screening peptides showed affinities for PLK1-PBD in a competitive binding assay. In particular, peptide 5 exhibited an approximately 100-fold increase in inhibitory activity (IC50 = 70 nM), as compared with the control poloboxtide. Moreover, cell cycle experiments indicated that peptide 5 effectively inhibited the expression of p-Cdc25C and cell cycle regulatory proteins by affecting the function of PLK1-PBD, thereby inducing mitotic arrest at the G2/M phase. Overall, peptide 5 can serve as a potent lead for further investigation as PLK1-PBD inhibitors.

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