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In silico approaches using pharmacophore model combined with molecular docking for discovery of novel ULK1 inhibitors.

Authors
  • He, Siyu1, 2
  • Liu, Yang1
  • Li, Qihang1
  • Lyu, Weiping3
  • Feng, Feng4, 5
  • Guo, Qinglong2
  • Zhao, Li2
  • Sun, Haopeng1
  • 1 School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China. , (China)
  • 2 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis & Intervention, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China. , (China)
  • 3 Department of Pharmaceutical Analysis, Key Laboratory of Drug Quality Control & Pharmacovigilance, China Pharmaceutical University, Nanjing 211198, People's Republic of China. , (China)
  • 4 Jiangsu Food & Pharmaceuticals Science College, Institute of Food & Pharmaceuticals Research, 223005, People's Republic of China. , (China)
  • 5 Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People's Republic of China. , (China)
Type
Published Article
Journal
Future Medicinal Chemistry
Publisher
"Future Science, LTD"
Publication Date
Feb 01, 2021
Volume
13
Issue
4
Pages
341–361
Identifiers
DOI: 10.4155/fmc-2020-0253
PMID: 33427493
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Background: Discovery of effective autophagy-initiating kinase ULK1 inhibitors has attracted more and more attention in cancer treatment. Methodology & results: The present study describes the application of a pharmacophore-based virtual screening and structure-based docking approach guided drug design. Compound U-2 exhibited a nanomolar range of IC50 against the ULK1 target. Molecular dynamics simulation was used to assess the quality of docking studies. The determinants of binding affinity were investigated, and a different binding pattern was observed. Subsequently, prediction properties of ADMET (absorption, distribution, metabolism, excretion and toxicity) and hepatotoxicity in vitro studies indicated that U-2 possessed good drug-like properties. Moreover, western blot analysis indicated that the compound inhibited autophagic flux in cells. Conclusion: The present study provides an appropriate guideline for discovering novel ULK1 inhibitors. The novel compound may serve as a good starting point for further development and optimizations.

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