Novel quinazoline–chromene hybrids as anticancer agents: Synthesis, biological activity, molecular docking, dynamics and ADME studies

Abstract

In this study, new quinazoline–chromene hybrid compounds were synthesized. The cytotoxic effects on cell viability of the hybrid compounds were tested against A549 human lung adenocarcinoma and BEAS‐2B healthy bronchial epithelial cell lines in vitro. In addition, the ability of the active compounds to inhibit cell migration was tested. Molecular docking studies were performed to evaluate the ligand–protein interactions, and molecular dynamics simulations were performed to determine the interactions and stability of ligand–protein complexes. In silico absorption, distribution, metabolism, and excretion (ADME) studies were conducted to estimate the drug‐likeness of the compounds. Compounds 4 (IC50 = 51.2 µM) and 5 (IC50 = 44.2 µM) were found to be the most active agents against A549 cells. They are found to be more selective against A549 cells than the reference drug doxorubicin. They also have the ability to significantly inhibit cell migration. They have the best docking scores against epidermal growth factor receptor (EGFR) (−11.300 and −11.226 kcal/mol) and vascular endothelial growth factor receptor 2 (VEGFR2) (−10.987 and −11.247 kcal/mol), respectively. In MD simulations, compounds 4 and 5 have strong hydrogen bond interactions above 80% of simulation times and showed a low ligand root mean square deviation (RMSD) around 2 Å. According to the ADME analysis, compounds 4 and 5 exhibit excellent drug‐likeness and pharmacokinetic characteristics.

4‐Furfuryloxymethyl‐1,2,3‐triazol‐1‐yl‐acetohydrazide Hybrids as Cholinesterase and Carbonic Anhydrase Inhibitors: Synthesis, Characterization and Comprehensive Biological Activity Studies

“…To assess the accuracy of the binding pose reproduced through molecular docking, Root‐Mean Square Deviation (RMSD) values are commonly employed. Typically, poses with RMSD values less than 2 Å are considered indicative of a correct prediction of the bound structure, while values falling in the range of 2–3 Å are generally deemed acceptable [54] …”

“…The four protein targets used in this study are hAChE (PDB ID: 4M0E, resolution of 2.0 Å), hBChE (PDB ID: 5NN0, resolution of 2.10 Å), hCAI (PDB ID: 1AZM, resolution of 2.0 Å), and hCAII (PDB ID: 3HS4, resolution of 1.1 Å). The structures of the proteins were processed and prepared using the Protein Preparation Wizard module of Schrödinger maestro 13.5 [11,43, 54] . The minimized proteins were used for Induced‐Fit‐Docking (IFD) studies and ligands were directly docked to active site of proteins according to the IFD protocol [60] …”

“…The binding energy, represented by the IFD Score, was computed using standard parameters to produce 20 poses for each molecule through Glide XP docking. Subsequently, a comprehensive visual assessment was conducted for the generated poses in each protein‐ligand complex [54,62] …”

“…Molecular dynamic trajectories were generated and analyzed by using the Desmond's Simulation Interaction Diagram (SID) and the Root Mean Square Deviation (RMSD) of the Cα atoms of the protein and the heavy atoms of the ligand was analyzed using Desmond [54,66] …”

“…The in silico ADME properties of the selected compounds were performed utilized the QikProp panel of Maestro 13.5. QikProp provides values that compare the properties of new molecules to 95 % of known drugs [54,62] …”