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Free energy perturbation guided Synthesis with Biological Evaluation of Substituted Quinoline derivatives as small molecule L858R/T790M/C797S mutant EGFR inhibitors targeting resistance in Non-Small Cell Lung Cancer (NSCLC).

Authors
  • Karnik, Kshipra S1
  • Sarkate, Aniket P1
  • Tiwari, Shailee V2
  • Azad, Rajaram3
  • Wakte, Pravin S4
  • 1 Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, MS 431004, India. , (India)
  • 2 Department of Pharmaceutical Chemistry, Durgamata Institute of Pharmacy, Dharmapuri, Parbhani 431401, MS, India. , (India)
  • 3 Department of Animal Biology, University of Hyderabad, Hyderabad 500046, India. , (India)
  • 4 Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, MS 431004, India. Electronic address: [email protected] , (India)
Type
Published Article
Journal
Bioorganic chemistry
Publication Date
Oct 01, 2021
Volume
115
Pages
105226–105226
Identifiers
DOI: 10.1016/j.bioorg.2021.105226
PMID: 34364055
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Two different schemes of novel substituted quinoline derivatives were designed and synthesized via simple reaction steps and conditions. A comparative molecular docking study was carried out on two different types of EGFR enzymes which include wild-type (PDB: 4I23) and T790M mutated (PDB: 2JIV) respectively. Compounds were also validated upon T790M/C797S mutated (PDB ID: 5D41) EGFR enzyme at the allosteric binding site. Free energy perturbations were carried out to determine the absolute binding free energy of a protein-ligand complex in the form of ΔGbinding, which in turn provided 4ab and 5ad as the most potential contenders through the structural enhancement in the determined initial scaffolds. Anticancer activity of the synthesized derivatives was examined against HCC827, H1975 (L858R/T790M), A549, and HT-29 cell lines by standard MTT assay. Compound 4ad (6-chloro-2-(isoindolin-2-yl)-4-methylquinoline) has shown excellent inhibitory activities against mutant EGFR kinase with IC50 value 0.91 µM. The potency of compounds 4ab, 4ad and 5adwas compared throughan insilicoADMET study. Copyright © 2021 Elsevier Inc. All rights reserved.

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