2. Academic Validation
  3. In Silico Discovery of a Small Molecule Suppressing Lung Carcinoma A549 Cells Proliferation and Inducing Autophagy via mTOR Pathway Inhibition

In Silico Discovery of a Small Molecule Suppressing Lung Carcinoma A549 Cells Proliferation and Inducing Autophagy via mTOR Pathway Inhibition

  • Mol Pharm. 2018 Nov 5;15(11):5427-5436. doi: 10.1021/acs.molpharmaceut.8b00996.
Jiyuan Liu 1,  Li Liu 2 3,  Zhen Tian 4,  Yifan Li 1,  Changhong Shi 3,  Junling Shi 2,  Sanhua Wei 5,  Yong Zhao 3,  Caiqing Zhang 3,  Bing Bai 3,  Zhinan Chen 6,  Hai Zhang 3 6
Affiliations

Affiliations

  • 1 Key Laboratory of Plant Protection Resources & Pest Management of the Ministry of Education, College of Plant Protection , Northwest A&F University , Yangling , 712100 Shaanxi , China.
  • 2 Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences , Northwestern Polytechnical University , 127 Youyi West Road , Xi'an , Shaanxi Province 710072 , China.
  • 3 Laboratory Animal Center , Air Force Medical University , No. 169 Changle West Road , Xi'an , Shaanxi Province 710032 , China.
  • 4 College of Horticulture and Plant Protection , Yangzhou University , Wenhui East Road, NO. 48 , Yangzhou , Jiangsu Province 225009 , China.
  • 5 Department of Clinical Laboratory and Research Center, Tangdu Hospital , Air Force Medical University , No. 569 Xinsi Road , Xi'an , Shaanxi 710038 , China.
  • 6 National Translational Science Center for Molecular Medicine, Department of Cell Biology, School of Basic Medicine , Air Force Medical University , Xi'an , Shaanxi Province 710032 , China.
PMID: 30346178 DOI: 10.1021/acs.molpharmaceut.8b00996
Abstract

Mammalian target of rapamycin (mTOR) kinase is vital to the regulation of cell growth and proliferation, and it has been taken as a promising target to develop Cancer therapies. By reference to the crystal structure of mTOR-PP242, we explored to discover potential ATP-competitive inhibitors of mTOR. Through the integrated use of multiple in silico screenings, the tremendous amount of compounds from the SPECS database were finally reduced to 30. After several rounds of convincing biological tests in A549 cells, the newfound C-4 was identified as a potential ATP-competitive inhibitor of mTOR. Besides A549 cell proliferation suppression caused by C-4, Autophagy was also determined through autophagosome observation and Autophagy flux detection in C-4 treated A549 cells. We demonstrated that C-4 could inhibit cell growth and proliferation, and this inhibition may be associated with Autophagy.

Keywords

autophagy; inhibitor; mTOR kinase; pharmacophore modeling; virtual screening.

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