Exploring the interaction between epidermal growth factor receptor tyrosine kinase and some of the synthesized inhibitors using combination of in-silico and in-vitro cytotoxicity methods

Abstract

Quinazoline derivatives are potent inhibitors of human epidermal growth factor receptor (EGFR) as anticancer agents. In this study, the cytotoxic effects of a new series of synthesized quinazoline derivatives were evaluated using MTT assay against MCF-7 and HT-29 cell lines. Using molecular docking, the binding modes of all compounds were analyzed at the binding site of EGFR. Based on the results, the compounds L1, L2, L4, L5, L6, L7, L10, L15, and L18 may be promising EGFR inhibitors based on docking score and hydrogen bonds. Consistent with the experimental data, Met769 is recognized as a key residue in the binding of potential inhibitors. According to the MTT cytotoxicity assays, Lipinski's rule of five (RO5), absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters, and docking studies, three compounds L4, L15, and L10 with IC50 values of 80, 60, and 1 μM against the MCF-7 were selected for further comparative assessments. The dynamics of free EGFR, and selected ligand-EGFR complexes were investigated using molecular dynamics (MD) simulation studies. The results indicated that the three compounds bound to EGFR active site in a stable manner during the simulation through the formation of new hydrogen bonds with Phe699, Leu694, Gly700, Lys721, Met769, Arg817, and Asp831 with the superiority of compound L15. These features can promote future drug candidate designing to produce better derivatives in the search for the anticancer agents.

Anticancer Studies of Newly Synthesized Thiazole Derivatives: Synthesis, Characterization, Biological Activity, and Molecular Docking

“…Also, compound 4c formed a hydrogen bonding (H-donor and H-acceptor) with amino acids existing in the active site of the aromatase enzyme, such as ARG 435 (arginine 435) and TRP 141 (tryptophane 141), in a distance (bond length) ranging from 2.99 to 3.56 (A 0 ), a s shown in Table 3 and In addition, the molecular docking results of synthesized compounds (4a-c) and 5 against "EGFR" (PDB: 1EPG) revealed a moderate docking scores by creating H-bonding, Arene-H (pi-H), and Arene-cation (pi-cation) interactions (Table 4) compared to the interactions of these compounds with the aromatase enzyme (Table 3). Compound 4c showed a favorable docking score (−4.72) kcal/mol and RMSD (1.33) by forming a hydrogen bond with CYS 20 (cysteine 20), and pi-cation interactions with ASN 1 (asparagine 1) exist in the active site of "EGFR" (Table 4 and Figure 5) in agreement with erlotinib (−7.09 kcal/mol) as potential EGFR inhibitors [53]. In comparison to Sorafenib (−9.7) kcal/mol and kenpaullone (−9.4) kcal/mol as CDK2 enzyme inhibitors, further docking tests of the synthesized compounds (4a-c) and 5 against CDK2 (cyclin-dependent kinase-2) revealed moderate docking scores [54].…”

“…The most thorough understanding of ligand-receptor interactions is provided by molecular docking studies. The binding of ligands to the active site of cellular target proteins is the basis for the biological actions of chemically created substances [52][53][54][55]61,62]. For clarification of the method by which the produced chemicals conjugate with aromatase, EGFR, CDK2, and Bcl-2 proteins and act as inhibitors to prevent the growth, proliferation, and development of cancer cells by inhibiting estrogen production and onset of the cell cycle stall in cancer cells, a molecular docking program was used to determine how the synthesized compounds 4a-c and 5 interacted with the selected docked proteins.…”

The effect of mutation on neurotoxicity reduction of new chimeric reteplase, a computational study

“…To analyze docking complexes, the interaction between ATD and each reteplase was analyzed after simulation. These analyses are including root mean squared fluctuation (RMSF), root means squared deviation (RMSD), average solvent accessible surface area (SASA), the radius of gyration (Rg), the minimal distance between two proteins in each docking complex, number of contacts between residues of two proteins in each docking complex, the total number of intermolecular hydrogen bonds formed between two proteins ( 23 24 25 ). Also, The molecular mechanics Poisson-Boltzmann surface area (MMPBSA) method was used which has been broadly applied as an effective and trustworthy free energy simulation method for the assessment of molecular interactions like protein-ligand binding or protein-protein interactions ( 26 ).…”

Identification of Herbacetin as L858R and T790M inhibitor in Breast Cancer

“…Molecular docking studies can assist identify the locations of interaction and the common interaction between an inhibitor and the epidermal growth factor receptor (Nasab et al, 2018). The stability of the docked complex can be better understood by determining the fit value because the two are directly proportional to one another.…”