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).

Autor: Karnik KS; Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, MS 431004, India., Sarkate AP; Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, MS 431004, India., Tiwari SV; Department of Pharmaceutical Chemistry, Durgamata Institute of Pharmacy, Dharmapuri, Parbhani 431401, MS, India., Azad R; Department of Animal Biology, University of Hyderabad, Hyderabad 500046, India., Wakte PS; Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, MS 431004, India. Electronic address: pswkshipra16@gmail.com.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2021 Oct; Vol. 115, pp. 105226. Date of Electronic Publication: 2021 Jul 31.
DOI: 10.1016/j.bioorg.2021.105226
Abstrakt: 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 ΔG binding , 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 IC 50 value 0.91 µM. The potency of compounds 4ab, 4ad and 5adwas compared throughan insilicoADMET study.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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