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)

Kshipra S Karnik; Aniket P Sarkate; Shailee V Tiwari; Rajaram Azad; Pravin S Wakte

doi:10.1016/j.bioorg.2021.105226

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)

Bioorg Chem. 2021 Oct:115:105226. doi: 10.1016/j.bioorg.2021.105226. Epub 2021 Jul 31.

Authors

Kshipra S Karnik¹, Aniket P Sarkate¹, Shailee V Tiwari², Rajaram Azad³, Pravin S Wakte⁴

Affiliations

¹ Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, MS 431004, India.
² Department of Pharmaceutical Chemistry, Durgamata Institute of Pharmacy, Dharmapuri, Parbhani 431401, MS, India.
³ Department of Animal Biology, University of Hyderabad, Hyderabad 500046, India.
⁴ Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, MS 431004, India. Electronic address: pswkshipra16@gmail.com.

PMID: 34364055
DOI: 10.1016/j.bioorg.2021.105226

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 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 IC₅₀ value 0.91 µM. The potency of compounds 4ab, 4ad and 5adwas compared throughan insilicoADMET study.

Keywords: ADMET; Anticancer activity; EGFR; Free energy perturbations; Molecular docking; Mutant; Quinoline.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm / drug effects
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / genetics
ErbB Receptors / metabolism
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Molecular Structure
Mutation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quinolines / chemical synthesis
Quinolines / chemistry
Quinolines / pharmacology*
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship
Thermodynamics

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Quinolines
Small Molecule Libraries
quinoline
EGFR protein, human
ErbB Receptors