Molecular dynamic simulations based discovery and development of thiazolidin-4-one derivatives as EGFR inhibitors targeting resistance in non-small cell lung cancer (NSCLC)

Abstract

Targeting kinases with oncogenic driver mutations in malignancies with allosteric kinase inhibitors is a promising new treatment technique. EGFR inhibitors targeting the L858R/T790M/C797S mutation bearing thiazolidine-4-one scaffold were discovered, optimized, synthesized, and biologically evaluated. According to in silico and in vitro studies, compounds 6a and 6b resulted to be highly potent with IC₅₀ values of 120 nM and 134 nM and good selectivity. Compound 6a displayed significant antioxidant activity, with a DPPH radical scavenging value of 92.15%. The potency of compounds was also compared with ADMET and molecular dynamics simulations study. A comparative simulation of model protein and protein-ligand complex in presence and absence of compound 6a has been carried out.

Communicated by Ramaswamy H. Sarma

Keywords:

• EGFR
• allosteric
• thiazolidine-4-one
• ADMET
• molecular docking
• molecular dynamic simulations

Acknowledgement

The authors are thankful to The Head, Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004 (MS), India, for providing the laboratory facility.

Disclosure statement

The authors report no conflicts of interest in this work.

Data availability statement

The data that support the findings of this study are available from the corresponding author, P.S.W, upon reasonable request.

PDB codes

PDB ID: 5D41.

Additional information

Funding

The authors K. S. K and P. S. W. are thankful to Indian Council of Medical Research (ICMR) for providing funding in support of Senior Research Fellowship with Ref No: 3/2/2/33/2018/OnlineOncoFship/NCD-III.