Designing, molecular docking, and dynamics simulations studies of 1,2,3-triazole clamped Uracil-Coumarin hybrids against EGFR tyrosine kinase

Abstract

Since the last decade, hybrid drug strategies have attracted many researchers for their improved anti-cancer potential in comparison to single drug components. Complying to this approach, 28 novel Uracil-Coumarin hybrids with different sized linkers (2-5 carbon atoms) and substituents were designed to occupy the active site of protein epidermal growth factor receptor (EGFR) tyrosine kinase (Protein Data Bank ID: 1M17). Molecular docking studies were performed for all ligands (A1-D7) to identify the potential candidate using Schrödinger software. The relative binding affinity of hybrids toward EGFR was compared with standard Erlotinib on the basis of gScore and Emodel score. Positively, all the hybrids docked inside the cavity and showed significant interactions, compounds A6, A2, and A7 with short-chain linker (two carbon atoms) and halogen substituents were found to have more interactions and better docking score than standard Erlotinib. The visualization results depicted that compound A6 showed the highest affinity and formed the best binding pose to the target EGFR with gScore = -8.891 kcal/mol and Emodel score = -100.744 in comparison to standard Erlotinib (gScore of -8.538 kcal/mol and Emodel score = -80.588). Moreover, a molecular dynamics study also reveals that ligand A6 forms a stable complex with root mean square deviation (RMSD) of 0.3 nm and the plateau phase started just after 10 ns (time). Hence, the present research provides computational insights of Uracil-Coumarin hybrids as potential ligands against EGFR tyrosine kinase and in future in vitro investigations of these hybrids may prove their therapeutic potential against cancer.